Kavita Sarin, MD, PhD

All Publications

• Noninvasive virtual biopsy using micro-registered optical coherence tomography (OCT) in human subjects. Science advances Winetraub, Y., Van Vleck, A., Yuan, E., Terem, I., Zhao, J., Yu, C., Chan, W., Do, H., Shevidi, S., Mao, M., Yu, J., Hong, M., Blankenberg, E., Rieger, K. E., Chu, S., Aasi, S., Sarin, K. Y., de la Zerda, A. 2024; 10 (15): eadi5794

  Abstract

  Histological hematoxylin and eosin-stained (H&E) tissue sections are used as the gold standard for pathologic detection of cancer, tumor margin detection, and disease diagnosis. Producing H&E sections, however, is invasive and time-consuming. While deep learning has shown promise in virtual staining of unstained tissue slides, true virtual biopsy requires staining of images taken from intact tissue. In this work, we developed a micron-accuracy coregistration method [micro-registered optical coherence tomography (OCT)] that can take a two-dimensional (2D) H&E slide and find the exact corresponding section in a 3D OCT image taken from the original fresh tissue. We trained a conditional generative adversarial network using the paired dataset and showed high-fidelity conversion of noninvasive OCT images to virtually stained H&E slices in both 2D and 3D. Applying these trained neural networks to in vivo OCT images should enable physicians to readily incorporate OCT imaging into their clinical practice, reducing the number of unnecessary biopsy procedures.

  View details for DOI 10.1126/sciadv.adi5794

  View details for PubMedID 38598626

  View details for PubMedCentralID PMC11006228

• Dermatology Advances Into an Era of Precision Medicine. JAMA dermatology Wang, J. Y., Sarin, K. Y. 2021

  View details for DOI 10.1001/jamadermatol.2021.0024

  View details for PubMedID 34076667

• Genome-wide meta-analysis identifies eight new susceptibility loci for cutaneous squamous cell carcinoma. Nature communications Sarin, K. Y., Lin, Y. n., Daneshjou, R. n., Ziyatdinov, A. n., Thorleifsson, G. n., Rubin, A. n., Pardo, L. M., Wu, W. n., Khavari, P. A., Uitterlinden, A. n., Nijsten, T. n., Toland, A. E., Olafsson, J. H., Sigurgeirsson, B. n., Thorisdottir, K. n., Jorgensen, E. n., Whittemore, A. S., Kraft, P. n., Stacey, S. N., Stefansson, K. n., Asgari, M. M., Han, J. n. 2020; 11 (1): 820

  Abstract

  Cutaneous squamous cell carcinoma (SCC) is one of the most common cancers in the United States. Previous genome-wide association studies (GWAS) have identified 14 single nucleotide polymorphisms (SNPs) associated with cutaneous SCC. Here, we report the largest cutaneous SCC meta-analysis to date, representing six international cohorts and totaling 19,149 SCC cases and 680,049 controls. We discover eight novel loci associated with SCC, confirm all previously associated loci, and perform fine mapping of causal variants. The novel SNPs occur within skin-specific regulatory elements and implicate loci involved in cancer development, immune regulation, and keratinocyte differentiation in SCC susceptibility.

  View details for DOI 10.1038/s41467-020-14594-5

  View details for PubMedID 32041948

• Phenotypic heterogeneity of neurofibromatosis type 1 in a large international registry. JCI insight Tabata, M. M., Li, S. n., Knight, P. n., Bakker, A. n., Sarin, K. Y. 2020; 5 (16)

  Abstract

  Neurofibromatosis type 1 (NF1) is a rare genetic disorder, characterized by the development of benign and malignant nerve tumors. Although all individuals with NF1 harbor genetic alterations in the same gene, the clinical manifestations of NF1 are extremely heterogeneous even among individuals who carry identical genetic defects. In order to deepen the understanding of phenotypic manifestations in NF1, we comprehensively characterized the prevalence of 18 phenotypic traits in 2051 adults with NF1 from the Children's Tumor Foundation's NF1 registry. We further investigated the coassociation of traits and found positive correlations between spinal neurofibromas and pain, spinal neurofibromas and scoliosis, spinal neurofibromas and optic gliomas, and optic gliomas and sphenoid wing dysplasia. Furthermore, with increasing numbers of cutaneous neurofibromas, the odds ratio of malignant peripheral nerve sheath tumor increased. Phenotypic clustering revealed 6 phenotypic patient cluster subtypes: mild, freckling predominant, neurofibroma predominant, skeletal predominant, late-onset neural severe, and early-onset neural severe, highlighting potential phenotypic subtypes within NF1. Together, our results support potential shared molecular pathogenesis for certain clinical manifestations and illustrate the utility of disease registries for understanding rare diseases.

  View details for DOI 10.1172/jci.insight.136262

  View details for PubMedID 32814709

• Genetic mutations underlying phenotypic plasticity in basosquamous carcinoma Journal of Investigative Dermatology Chiang, A., Tan, C. Z., Kuonen, F., Hodgkinson, L. M., Chiang, F., Cho, R. J., South, A. P., Tang, J. Y., Chang, A. L., Rieger, K. E., Oro, A. E., Sarin, K. Y. 2019

  View details for DOI 10.1016/j.jid.2019.03.1163

• Identification of Atorvastatin for Moderate to Severe Hidradenitis through Drug Repositioning Using Public Gene Expression Datasets JOURNAL OF INVESTIGATIVE DERMATOLOGY Kuo, K. Y., Cho, H., Sarin, K. Y. 2018; 138 (5): 1209–12

  View details for PubMedID 29247661

• Detecting Chemotherapeutic Skin Adverse Reactions in Social Health Networks Using Deep Learning. JAMA oncology Ransohoff, J. D., Nikfarjam, A. n., Jones, E. n., Loew, B. n., Kwong, B. Y., Sarin, K. Y., Shah, N. H. 2018; 4 (4): 581–83

  View details for PubMedID 29494731

• Postzygotic Mutations in Beta-Actin are Associated with Becker's Nevus and Becker's Nevus Syndrome. journal of investigative dermatology Cai, E. D., Sun, B. K., Chiang, A., Rogers, A., Bernet, L., Cheng, B., Teng, J., Rieger, K. E., Sarin, K. Y. 2017

  View details for DOI 10.1016/j.jid.2017.03.017

  View details for PubMedID 28347698

• Two-stage genome-wide association study identifies a novel susceptibility locus associated with melanoma. Oncotarget Ransohoff, K. J., Wu, W., Cho, H. G., Chahal, H. C., Lin, Y., Dai, H., Amos, C. I., Lee, J. E., Tang, J. Y., Hinds, D. A., Han, J., Wei, Q., Sarin, K. Y. 2017

  Abstract

  Genome-wide association studies have identified 21 susceptibility loci associated with melanoma. These loci implicate genes affecting pigmentation, nevus count, telomere maintenance, and DNA repair in melanoma risk. Here, we report the results of a two-stage genome-wide association study of melanoma. The stage 1 discovery phase consisted of 4,842 self-reported melanoma cases and 286,565 controls of European ancestry from the 23andMe research cohort and the stage 2 replication phase consisted of 1,804 melanoma cases and 1,026 controls from the University of Texas M.D. Anderson Cancer Center. We performed a combined meta-analysis totaling 6,628 melanoma cases and 287,591 controls. Our study replicates 20 of 21 previously known melanoma-loci and confirms the association of the telomerase reverse transcriptase, TERT, with melanoma susceptibility at genome-wide significance. In addition, we uncover a novel polymorphism, rs187843643 (OR = 1.96; 95% CI = [1.54, 2.48]; P = 3.53 x 10-8), associated with melanoma. The SNP rs187842643 lies within a noncoding RNA 177kb downstream of BASP1 (brain associated protein-1). We find that BASP1 expression is suppressed in melanoma as compared with benign nevi, providing additional evidence for a putative role in melanoma pathogenesis.

  View details for DOI 10.18632/oncotarget.15230

  View details for PubMedID 28212542

  View details for PubMedCentralID PMC5392271

• Genomic Stability in Syndromic Basal Cell Carcinoma. The Journal of investigative dermatology Chiang, A. n., Jaju, P. D., Batra, P. n., Rezaee, M. n., Epstein, E. H., Tang, J. Y., Sarin, K. Y. 2017

  Abstract

  Basal cell cancers (BCCs) are characterized by up-regulation of Hedgehog pathway through loss of Patched1 or activation of Smoothened, and smoothened-inhibitors such as vismodegib are effective therapies for advanced BCCs. Although most BCCs are sporadic, rare individuals with Basal Cell Nevus Syndrome (BCNS) harbor germline defects in Patched1 and develop up to hundreds of tumors that are histopathologically indistinguishable from sporadic BCCs. Interestingly, BCNS-BCCs are more responsive to Smoothened-inhibitors than sporadic BCCs, with minimal development of resistance. Given differences in clinical course and therapy response, we sought to characterize BCCs in the setting of BCNS. We found that BCNS individuals with low-tumor burden demonstrated significantly fewer UV signature somatic mutations and lower overall somatic mutational load compared to BCNS individuals with high-burden, supporting a role of UV exposure in driving BCC development in BCNS individuals. However, compared with sporadic BCCs, BCNS-BCCs have a significantly lower mutational load, lower proportion of ultraviolet mutagenesis, increased genomic stability, and harbor fewer functionally resistant Smoothened mutations at baseline, explaining why BCNS-BCCs lack intrinsic resistance to Smoothened-inhibitors. BCNS-BCCs appear to have reduced mutator phenotype as compared with sporadic BCCs, which may contribute to their relatively more indolent clinical course and responsiveness to therapy.

  View details for PubMedID 29111235

• Identification of Alpha-Adrenergic Agonists as Potential Therapeutic Agents for Dermatomyositis through Drug-Repurposing Using Public Expression Datasets. journal of investigative dermatology Cho, H. G., Fiorentino, D., Lewis, M., Sirota, M., Sarin, K. Y. 2016; 136 (7): 1517-1520

  View details for DOI 10.1016/j.jid.2016.03.001

  View details for PubMedID 26975725

  View details for PubMedCentralID PMC5399882

• Genome-wide association study identifies 14 novel risk alleles associated with basal cell carcinoma. Nature communications Chahal, H. S., Wu, W., Ransohoff, K. J., Yang, L., Hedlin, H., Desai, M., Lin, Y., Dai, H., Qureshi, A. A., Li, W., Kraft, P., Hinds, D. A., Tang, J. Y., Han, J., Sarin, K. Y. 2016; 7: 12510-?

  Abstract

  Basal cell carcinoma (BCC) is the most common cancer worldwide with an annual incidence of 2.8 million cases in the United States alone. Previous studies have demonstrated an association between 21 distinct genetic loci and BCC risk. Here, we report the results of a two-stage genome-wide association study of BCC, totalling 17,187 cases and 287,054 controls. We confirm 17 previously reported loci and identify 14 new susceptibility loci reaching genome-wide significance (P<5 × 10(-8), logistic regression). These newly associated SNPs lie within predicted keratinocyte regulatory elements and in expression quantitative trait loci; furthermore, we identify candidate genes and non-coding RNAs involved in telomere maintenance, immune regulation and tumour progression, providing deeper insight into the pathogenesis of BCC.

  View details for DOI 10.1038/ncomms12510

  View details for PubMedID 27539887

  View details for PubMedCentralID PMC4992160

• Genome-wide association study identifies novel susceptibility loci for cutaneous squamous cell carcinoma. Nature communications Chahal, H. S., Lin, Y., Ransohoff, K. J., Hinds, D. A., Wu, W., Dai, H., Qureshi, A. A., Li, W., Kraft, P., Tang, J. Y., Han, J., Sarin, K. Y. 2016; 7: 12048-?

  Abstract

  Cutaneous squamous cell carcinoma represents the second most common cutaneous malignancy, affecting 7-11% of Caucasians in the United States. The genetic determinants of susceptibility to cutaneous squamous cell carcinoma remain largely unknown. Here we report the results of a two-stage genome-wide association study of cutaneous squamous cell carcinoma, totalling 7,404 cases and 292,076 controls. Eleven loci reached genome-wide significance (P<5 × 10(-8)) including seven previously confirmed pigmentation-related loci: MC1R, ASIP, TYR, SLC45A2, OCA2, IRF4 and BNC2. We identify an additional four susceptibility loci: 11q23.3 CADM1, a metastasis suppressor gene involved in modifying tumour interaction with cell-mediated immunity; 2p22.3; 7p21.1 AHR, the dioxin receptor involved in anti-apoptotic pathways and melanoma progression; and 9q34.3 SEC16A, a putative oncogene with roles in secretion and cellular proliferation. These susceptibility loci provide deeper insight into the pathogenesis of squamous cell carcinoma.

  View details for DOI 10.1038/ncomms12048

  View details for PubMedID 27424798

  View details for PubMedCentralID PMC4960294

• Mutations in the Kinetochore Gene KNSTRN in Basal Cell Carcinoma. journal of investigative dermatology Jaju, P. D., Nguyen, C. B., Mah, A. M., Atwood, S. X., Li, J., Zia, A., Chang, A. L., Oro, A. E., Tang, J. Y., Lee, C. S., Sarin, K. Y. 2015; 135 (12): 3197-3200

  View details for DOI 10.1038/jid.2015.339

  View details for PubMedID 26348826

• Squamous Change in Basal-Cell Carcinoma with Drug Resistance NEW ENGLAND JOURNAL OF MEDICINE Ransohoff, K. J., Tang, J. Y., Sarin, K. Y. 2015; 373 (11): 1079-1082

  View details for DOI 10.1056/NEJMc1504261

  View details for Web of Science ID 000360959000024

• Smoothened variants explain the majority of drug resistance in Basal cell carcinoma. Cancer cell Atwood, S. X., Sarin, K. Y., Whitson, R. J., Li, J. R., Kim, G., Rezaee, M., Ally, M. S., Kim, J., Yao, C., Chang, A. L., Oro, A. E., Tang, J. Y. 2015; 27 (3): 342-353

  Abstract

  Advanced basal cell carcinomas (BCCs) frequently acquire resistance to Smoothened (SMO) inhibitors through unknown mechanisms. Here we identify SMO mutations in 50% (22 of 44) of resistant BCCs and show that these mutations maintain Hedgehog signaling in the presence of SMO inhibitors. Alterations include four ligand binding pocket mutations defining sites of inhibitor binding and four variants conferring constitutive activity and inhibitor resistance, illuminating pivotal residues that ensure receptor autoinhibition. In the presence of a SMO inhibitor, tumor cells containing either class of SMO mutants effectively outcompete cells containing the wild-type SMO. Finally, we show that both classes of SMO variants respond to aPKC-ι/λ or GLI2 inhibitors that operate downstream of SMO, setting the stage for the clinical use of GLI antagonists.

  View details for DOI 10.1016/j.ccell.2015.02.002

  View details for PubMedID 25759020

• Impaired innate and adaptive immune responses to BNT162b2 SARS-CoV-2 vaccination in systemic lupus erythematosus. JCI insight Sarin, K. Y., Zheng, H., Chaichian, Y., Arunachalam, P. S., Swaminathan, G., Eschholz, A., Gao, F., Wirz, O. F., Lam, B., Yang, E., Lee, L. W., Feng, A., Lewis, M. A., Lin, J., Maecker, H. T., Boyd, S. D., Davis, M. M., Nadeau, K. C., Pulendran, B., Khatri, P., Utz, P. J., Zaba, L. C. 2024; 9 (5)

  Abstract

  Understanding the immune responses to SARS-CoV-2 vaccination is critical to optimizing vaccination strategies for individuals with autoimmune diseases, such as systemic lupus erythematosus (SLE). Here, we comprehensively analyzed innate and adaptive immune responses in 19 patients with SLE receiving a complete 2-dose Pfizer-BioNTech mRNA vaccine (BNT162b2) regimen compared with a control cohort of 56 healthy control (HC) volunteers. Patients with SLE exhibited impaired neutralizing antibody production and antigen-specific CD4+ and CD8+ T cell responses relative to HC. Interestingly, antibody responses were only altered in patients with SLE treated with immunosuppressive therapies, whereas impairment of antigen-specific CD4+ and CD8+ T cell numbers was independent of medication. Patients with SLE also displayed reduced levels of circulating CXC motif chemokine ligands, CXCL9, CXCL10, CXCL11, and IFN-γ after secondary vaccination as well as downregulation of gene expression pathways indicative of compromised innate immune responses. Single-cell RNA-Seq analysis reveals that patients with SLE showed reduced levels of a vaccine-inducible monocyte population characterized by overexpression of IFN-response transcription factors. Thus, although 2 doses of BNT162b2 induced relatively robust immune responses in patients with SLE, our data demonstrate impairment of both innate and adaptive immune responses relative to HC, highlighting a need for population-specific vaccination studies.

  View details for DOI 10.1172/jci.insight.176556

  View details for PubMedID 38456511

• Toward risk stratification and personalized therapy for neurofibromas in neurofibromatosis type 1. The British journal of dermatology Romo, C. G., Sarin, K. Y., Blakeley, J. O. 2023

  View details for DOI 10.1093/bjd/ljad452

  View details for PubMedID 38123358

• A core outcome domain set to assess cutaneous neurofibromas related to neurofibromatosis type 1 in clinical trials. The British journal of dermatology Fertitta, L., Bergqvist, C., Sarin, K., Plotkin, S. R., Moertel, C., Petersen, A. J., Cannon, A., Berman, Y., Pichard, D. C., Röhl, C., Lessing, A., Brizion, B., Peiffer, B., Ravaud, P., Tran, V. T., Armand, M. L., Moryousef, S., Ferkal, S., Jannic, A., Ezzedine, K., Wolkenstein, P. 2023

  Abstract

  Cutaneous neurofibromas (cNF) are considered one of the highest burdens of neurofibromatosis type 1 (NF1). To date, no medical treatment can cure cNF or prevent their development. In that context, there is an urgent need to prepare and standardize the methodology of future trials targeting cNF.The objective was to develop a core outcome domain set suitable for all clinical trials targeting NF1-associated cNF.The validated approach of this work consisted of a three-phase methodology: i) generating the domains (systematic review of literature (SRL) and qualitative studies), ii) agreeing (three-round international e-Delphi consensus process, working groups), and iii) voting.i) The SLR and the qualitative studies (three types of focus groups and a French e-survey with 234 participants) resulted in a preliminary list of 31 candidate items and their corresponding definitions. ii) A total of 229 individuals from 29 countries participated in the first round of the e-Delphi: 71 patients, relatives or representatives (31.0%), 130 health-care professionals (HCP, 56.8%) and 28 researchers, representatives of a drug regulatory authority, industry or pharmaceutical company representatives or journal editors (12.2%). The overall participation rate was 74%. Between rounds 2 and 3, international workshops were held to better understand the disagreement amongst stakeholders. This phase led to the identification of 19 items as outcome sub-domains. iii) The items were fused to create 4 outcome domains ("clinical assessment", "daily life impact", "patient satisfaction" and "perception of health") and prioritized. The 7 items which did not reach consensus were decided to be marked for the research agenda. The final core outcome domain set reached 100% of the votes of the steering committee members.Although numerous outcomes can be explored in studies related to cNF in NF1, the present study offers 4 outcome domains that should be reported in all trial studies, agreed upon by international patients, relatives and representatives of patients, HCP, researchers, representatives of drug regulatory authorities or pharmaceutical companies, and journal editors. The next step will include the development of a set of core outcome measurement instruments to further standardize how these outcomes should be assessed.

  View details for DOI 10.1093/bjd/ljad397

  View details for PubMedID 37877514

• Development of a MEK inhibitor, NFX-179, as a chemoprevention agent for squamous cell carcinoma. Science translational medicine Sarin, K. Y., Kincaid, J., Sell, B., Shahryari, J., Duncton, M. A., Morefield, E., Sun, W., Prieto, K., Chavez-Chiang, O., de Moran Segura, C., Nguyen, J., Bronson, R. T., Plotkin, S. R., Kochendoerfer, G. G., Fenn, P., Wootton, M. A., Powala, C., de Souza, M. P., Tsai, K. Y. 2023; 15 (717): eade1844

  Abstract

  Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer. Although cSCC contributes to substantial morbidity and mortality in high-risk individuals, deployment of otherwise effective chemoprevention of cSCC is limited by toxicities. Our systematic computational drug repurposing screen predicted that selumetinib, a MAPK (mitogen-activated protein kinase) kinase inhibitor (MEKi), would reverse transcriptional signatures associated with cSCC development, consistent with our genomic analysis implicating MEK as a chemoprevention target. Although systemic MEKi suppresses the formation of cSCC in mice, systemic MEKi can cause severe adverse effects. Here, we report the development of a metabolically labile MEKi, NFX-179, designed to potently and selectively suppress the MAPK pathway in the skin before rapid metabolism in the systemic circulation. NFX-179 was identified on the basis of its biochemical and cellular potency, selectivity, and rapid metabolism upon systemic absorption. In our ultraviolet-induced cSCC mouse model, topical application of NFX-179 gel reduced the formation of new cSCCs by an average of 60% at doses of 0.1% and greater at 28 days. We further confirmed the localized nature of these effects in an additional split-mouse randomized controlled study where suppression of cSCC was observed only in drug-treated areas. No toxicities were observed. NFX-179 inhibits the growth of human SCC cell lines in a dose-dependent manner, and topical NFX-179 application penetrates human skin and inhibits MAPK signaling in human cSCC explants. Together, our data provide a compelling rationale for using topical MEK inhibition through the application of NFX-179 gel as an effective strategy for cSCC chemoprevention.

  View details for DOI 10.1126/scitranslmed.ade1844

  View details for PubMedID 37820007

• Development of a digital tool for home-based monitoring of skin disease for older adults. Skin health and disease van Egmond, S., Cai, Z. R., Nava, V., Joy de Vere Hunt, I., Rapaport, B. R., Ko, J., Chiou, A. S., Sarin, K., Tang, J., Zhang, L., Linos, E. 2023; 3 (5): e235

  Abstract

  We developed a digital tool for home-based monitoring of skin disease, our digital tool. In the current observational pilot study, we found that DORA is feasible to use in practice, as it has a high patient compliance, retention and satisfaction. Clinicans rated the photos generally good quality or perfect quality. These results show that the digital health tool DORA can easily be used by patients to send photos to their dermatologist, which could reduce unnecessary clinical visits. It may also be used in other settings where digital literacy barriers and unequal access to dermatologists contribute to healthcare disparities.

  View details for DOI 10.1002/ski2.235

  View details for PubMedID 37799368

  View details for PubMedCentralID PMC10549824

• Hidradenitis suppurativa and Ehlers-Danlos syndrome: A case-control study. JAAD international Hua, V. J., Li, S., Sarin, K. Y., Aleshin, M. 2023; 12: 70-71

  View details for DOI 10.1016/j.jdin.2023.03.008

  View details for PubMedID 37274386

  View details for PubMedCentralID PMC10236182

• Cross-comparison of inflammatory skin disease transcriptomics identifies PTEN as a pathogenic disease classifier in cutaneous lupus erythematosus. The Journal of investigative dermatology Aevermann, B. D., Di Domizio, J., Olah, P., Saidoune, F., Armstrong, J. M., Bachelez, H., Barker, J., Haniffa, M., Julia, V., Juul, K., Krishnaswamy, J. K., Litman, T., Parsons, I., Sarin, K. Y., Schmuth, M., Sierra, M., Simpson, M., Homey, B., Griffiths, C. E., Scheuermann, R. H., Gilliet, M. 2023

  Abstract

  Tissue transcriptomics is used to uncover molecular dysregulations underlying diseases. However, the majority of transcriptomics studies focus on single diseases with limited relevance for understanding the molecular relationship between diseases or for identifying disease-specific markers. Here, we used a normalization approach to compare gene expression across nine inflammatory skin diseases. The normalized datasets were found to retain differential expression signals that allowed unsupervised disease clustering and identification of disease-specific gene signatures. Using the NS-Forest algorithm, we identified a minimal set of biomarkers and validated their use as diagnostic disease classifier. Among them, PTEN was identified as being a specific marker for cutaneous lupus erythematosus (CLE) and found to be strongly expressed by lesional keratinocytes in association with pathogenic type I interferons (IFNs). In fact, PTEN facilitated expression of IFN-β and IFN-κ in keratinocytes by promoting activation and nuclear translocation of IRF3. Thus, cross-comparison of tissue transcriptomics is a valid strategy to establish a molecular disease classification and identify pathogenic disease biomarkers.

  View details for DOI 10.1016/j.jid.2023.06.211

  View details for PubMedID 37598867

• A Call for Discovery and Therapeutic Development for Cutaneous Neurofibromas. The Journal of investigative dermatology Blakeley, J. O., Le, L. Q., Lee, S. Y., Ly, I., Rhodes, S. D., Romo, C. G., Sarin, K. Y., Staedtke, V., Steensma, M. R., Wolkenstein, P. 2023

  View details for DOI 10.1016/j.jid.2022.11.027

  View details for PubMedID 37354152

• Advances in cutaneous squamous cell carcinoma. Nature reviews. Cancer Winge, M. C., Kellman, L. N., Guo, K., Tang, J. Y., Swetter, S. M., Aasi, S. Z., Sarin, K. Y., Chang, A. L., Khavari, P. A. 2023

  Abstract

  Human malignancies arise predominantly in tissues of epithelial origin, where the stepwise transformation from healthy epithelium to premalignant dysplasia to invasive neoplasia involves sequential dysregulation of biological networks that govern essential functions of epithelial homeostasis. Cutaneous squamous cell carcinoma (cSCC) is a prototype epithelial malignancy, often with a high tumour mutational burden. A plethora of risk genes, dominated by UV-induced sun damage, drive disease progression in conjunction with stromal interactions and local immunomodulation, enabling continuous tumour growth. Recent studies have identified subpopulations of SCC cells that specifically interact with the tumour microenvironment. These advances, along with increased knowledge of the impact of germline genetics and somatic mutations on cSCC development, have led to a greater appreciation of the complexity of skin cancer pathogenesis and have enabled progress in neoadjuvant immunotherapy, which has improved pathological complete response rates. Although measures for the prevention and therapeutic management of cSCC are associated with clinical benefit, the prognosis remains poor for advanced disease. Elucidating how the genetic mechanisms that drive cSCC interact with the tumour microenvironment is a current focus in efforts to understand, prevent and treat cSCC.

  View details for DOI 10.1038/s41568-023-00583-5

  View details for PubMedID 37286893

  View details for PubMedCentralID 4833641

• Perspectives of adolescents with neurofibromatosis 1 and cutaneous neurofibromas: Implications for clinical trials. Clinical trials (London, England) Cannon, A., Sarin, K. Y., Petersen, A. K., Pichard, D. C., Wolters, P. L., Erickson, G., Lessing, A. J., Li, P., Rohl, C., Rosser, T., Widemann, B. C., Blakeley, J. O., Plotkin, S. R. 2023: 17407745231178839

  Abstract

  BACKGROUND/AIMS: More than 99% of individuals with neurofibromatosis 1 develop cutaneous neurofibromas, benign nerve sheath tumors that manifest as nodules on the skin. These cutaneous neurofibromas emerge with age, appearing most commonly in adolescence. Nevertheless, few data have been published on how adolescents with neurofibromatosis 1 feel about cutaneous neurofibromas. The purpose of this study was to assess the perspectives of adolescents with neurofibromatosis 1 and their caregivers regarding cutaneous neurofibroma morbidity, treatment options, and acceptable risks-benefits of treatment.METHODS: An online survey was distributed through the world's largest NF registry. Eligibility criteria included self-reported neurofibromatosis 1 diagnosis, adolescent child ages 12-17years,≥1 cutaneous neurofibroma, and ability to read English. The survey was designed to collect details about the adolescent's cutaneous neurofibromas, views on morbidity related to cutaneous neurofibromas, social and emotional impact of cutaneous neurofibromas, communication regarding cutaneous neurofibromas, and views regarding current and potential future cutaneous neurofibroma treatment.RESULTS: Survey respondents included 28 adolescents and 32 caregivers. Adolescents reported having several negative feelings about cutaneous neurofibromas, particularly feeling worried about the potential progression of their cutaneous neurofibromas (50%). Pruritus (34%), location (34%), appearance (31%), and number (31%) were the most bothersome cutaneous neurofibroma features. Topical medication (77%-96%), followed by oral medication (54%-93%), was the most preferred treatment modality. Adolescents and caregivers most often replied that cutaneous neurofibroma treatment should be initiated when cutaneous neurofibromas become bothersome. The majority of respondents were willing to treat cutaneous neurofibromas for at least 1 year (64%-75%). Adolescent and caregivers were least willing to risk pain (72%-78%) and nausea/vomiting (59%-81%) as a cutaneous neurofibroma treatment side effect.CONCLUSIONS: These data indicate that adolescents with neurofibromatosis 1 are negatively impacted by their cutaneous neurofibromas, and that both adolescents and their caregivers would be willing to try longer-term experimental treatments.

  View details for DOI 10.1177/17407745231178839

  View details for PubMedID 37269078

• RAS Signaling Gone Awry in the Skin: The Complex Role of RAS in Cutaneous Neurofibroma Pathogenesis, Emerging Biological Insights. The Journal of investigative dermatology Rhodes, S. D., McCormick, F., Cagan, R. L., Bakker, A., Staedtke, V., Ly, I., Steensma, M. R., Lee, S. Y., Romo, C. G., Blakeley, J. O., Sarin, K. Y. 2023

  Abstract

  Cutaneous neurofibromas (cNFs) are the most common tumor in people with the rasopathy neurofibromatosis type 1. They number in hundreds or even thousands throughout the body, and currently, there are no effective interventions to prevent or treat these skin tumors. To facilitate the identification of novel and effective therapies, essential studies including a more refined understanding of cNF biology and the role of RAS signaling and downstream effector pathways responsible for cNF initiation, growth, and maintenance are needed. This review highlights the current state of knowledge of RAS signaling in cNF pathogenesis and therapeutic development for cNF treatment.

  View details for DOI 10.1016/j.jid.2023.01.043

  View details for PubMedID 37245145

• cNF-Skindex in adults living with Neurofibromatosis 1: severity strata in France and validation in US adults. The Journal of investigative dermatology Fertitta, L., Sarin, K. Y., Bergqvist, C., Patel, E., Peiffer, B., Moryousef, S., Armand, M., Jannic, A., Ferkal, S., Ravaud, P., Tran, V., Blakeley, J. O., Romo, C. G., Ezzedine, K., Wolkenstein, P. 2023

  Abstract

  Cutaneous neurofibromas (cNF) contribute to the impairment of quality of life (QoL) in individuals with neurofibromatosis 1 (NF1). The cNF-Skindex, validated in a French population, specifically assesses the cNF-related QoL. In this study, we first defined severity strata using an anchoring approach based on patient's burden. In total, 209 patients answered the anchor question and the cNF-Skindex. We tested the agreement between the three strata, generated by all potential couples of cut-off values of the cNF-Skindex, and the three strata defined in the anchor question. The cut-off values 12 and 49 provided the highest Kappa value (K=0.685, 95%IC [0.604; 0.765]). Second, we validated the score and the strata in an US population using the answers of 220 French and 148 US adults. In the multivariable linear regression, the country of origin was not a factor associated with the score (p=0.297). The number of cNF along the different severity strata was similar between the French and the US populations. In conclusion, the stratification constitutes a powerful tool to better interpret the cNF-Skindex in daily practice and in clinical trials. This study validates its use in two populations which together constitute a large cohort of patients willing to participate in clinical research.

  View details for DOI 10.1016/j.jid.2023.04.014

  View details for PubMedID 37149083

• The type 1 interferon signature reflects multiple phenotypic and activity measures in dermatomyositis. Arthritis & rheumatology (Hoboken, N.J.) Tabata, M. M., Hodgkinson, L. M., Wu, T. T., Li, S., Huard, C., Zhao, S., Bennett, D., Johnson, J., Tierney, C., He, W., Buhlmann, J. E., Page, K. M., Johnson, K., Casciola-Rosen, L., Chung, L., Sarin, K. Y., Fiorentino, D. 2023

  Abstract

  The type 1 interferon (IFN1) pathway is upregulated in dermatomyositis (DM). We sought to define how organ-specific disease activity as well as autoantibodies and other clinical factors are independently associated with systemic IFN1 activity in adult patients with DM.RNA sequencing was performed on 355 whole blood samples collected from 202 well-phenotyped DM patients followed during the course of their clinical care. A previously defined 13-gene IFN1 score was modeled as a function of demographic, serologic and clinical variables using both cross-sectional and longitudinal data.The pattern of IFN1-driven transcriptional response was stereotyped across samples with a sequential modular activation pattern strikingly similar to SLE. The median IFN1 score was higher or lower in patients with anti-MDA5 or anti-Mi2 antibodies, respectively, compared to patients without these antibodies. Absolute IFN1 score was independently associated with muscle and skin disease activity, interstitial lung disease, and anti-MDA5 antibodies. Changes in the IFN1 score over time were significantly associated with changes in skin or muscle disease activity. Stratified analysis accounting for heterogeneity in organ involvement and antibody class revealed high correlation (ρ=0.84-0.95) between changes in the IFN1 score and skin disease activity.The IFN1 score independently associates with both skin and muscle disease activity as well as certain clinical and serologic features in DM. Accounting for the effect of muscle disease and anti-MDA5 status reveals that the IFN1 score is strongly correlated with skin disease activity and provides support for IFN1 blockade as a therapeutic strategy for DM. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/art.42526

  View details for PubMedID 37096447

• Association of multiple primary melanomas with malignancy risk: A population-based analysis of entries from the Surveillance, Epidemiology, and End Results program database during 1973-2014 JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Cai, E. D., Swetter, S. M., Sarin, K. Y. 2023; 88 (5): e211-e219

  View details for DOI 10.1016/j.jaad.2018.09.027

  View details for Web of Science ID 000983018900001

• Modulation of Inflammatory Proteins in Serum May Reflect Cutaneous Immune Responses in Cancer Immunotherapy. JID innovations : skin science from molecules to population health Han, J., Correa da Rosa, J., Agarwal, A., Owji, S., Yassky, D., Luu, Y., Shah, A., Estrada, Y., Ungar, J., Sarin, K. Y., Krueger, J. G., Gulati, N. 2023; 3 (2): 100179

  Abstract

  Diphencyprone (DPCP), a topical contact sensitizer, has shown efficacy in treating cutaneous melanoma metastases, including at times beyond the directly treated sites, but biomarkers indicative of treatment response have not been characterized. Thus, we performed a proteomic analysis of the skin and serum of five patients with cutaneous melanoma metastases treated with DPCP on days 0, 63, and 112 of the treatment course. In the serum, we found a significant upregulation (P < 0.05) in 13 of 96 assessed immuno-oncology proteins after DPCP treatment. Upregulated proteins included those of the T helper 1 axis (CXCL9, CXCL10), immune checkpoint proteins (PD-1), and various proteins with roles in promoting tumor immunity such as CD80 and TNFRSF4/9. Given the positive clinical response to topical treatment noted in the five patients studied, these proteins may represent prognostic biomarkers in the serum for evaluating the efficacy of DPCP treatment of cutaneous melanoma metastases. Because DPCP does not lead to nonspecific immune-related adverse events seen with immune checkpoint inhibitors, our study provides evidence for potential tumor-specific systemic immune activation and systemic antitumor effectors elicited by topical DPCP.

  View details for DOI 10.1016/j.xjidi.2022.100179

  View details for PubMedID 36876222

• Prevalence of allergic contact dermatitis following patch testing in patients with atopic dermatitis: a retrospective United States claims-based study. Journal of the American Academy of Dermatology Qian, M. F., Li, S., Honari, G., Sarin, K. Y., Chen, J. K. 2023

  View details for DOI 10.1016/j.jaad.2022.12.051

  View details for PubMedID 36775101

• Rapid Cellular-Resolution Skin Imaging with Optical Coherence Tomography Using All-Glass Multifocal Metasurfaces. ACS nano Zhao, J., Van Vleck, A., Winetraub, Y., Du, L., Han, Y., Aasi, S., Sarin, K. Y., de la Zerda, A. 2023

  Abstract

  Cellular-resolution optical coherence tomography (OCT) is a powerful tool offering noninvasive histology-like imaging. However, like other optical microscopy tools, a high numerical aperture (N.A.) lens is required to generate a tight focus, generating a narrow depth of field, which necessitates dynamic focusing and limiting the imaging speed. To overcome this limitation, we developed a metasurface platform that generates multiple axial foci, which multiplies the volumetric OCT imaging speed by offering several focal planes. This platform offers accurate and flexible control over the number, positions, and intensities of axial foci generated. All-glass metasurface optical elements 8 mm in diameter are fabricated from fused-silica wafers and implemented into our scanning OCT system. With a constant lateral resolution of 1.1 mum over all depths, the multifocal OCT triples the volumetric acquisition speed for dermatological imaging, while still clearly revealing features of stratum corneum, epidermal cells, and dermal-epidermal junctions and offering morphological information as diagnostic criteria for basal cell carcinoma. The imaging speed can be further improved in a sparse sample, e.g., 7-fold with a seven-foci beam. In summary, this work demonstrates the concept of metasurface-based multifocal OCT for rapid virtual biopsy, further providing insights for developing rapid volumetric imaging systems with high resolution and compact volume.

  View details for DOI 10.1021/acsnano.2c09542

  View details for PubMedID 36745734

• LY6D marks pre-existing resistant basosquamous tumor subpopulations. Nature communications Haensel, D., Gaddam, S., Li, N. Y., Gonzalez, F., Patel, T., Cloutier, J. M., Sarin, K. Y., Tang, J. Y., Rieger, K. E., Aasi, S. Z., Oro, A. E. 2022; 13 (1): 7520

  Abstract

  Improved response to canonical therapies requires a mechanistic understanding of dynamic tumor heterogeneity by identifying discrete cellular populations with enhanced cellular plasticity. We have previously demonstrated distinct resistance mechanisms in skin basal cell carcinomas, but a comprehensive understanding of the cellular states and markers associated with these populations remains poorly understood. Here we identify a pre-existing resistant cellular population in naive basal cell carcinoma tumors marked by the surface marker LY6D. LY6D+ tumor cells are spatially localized and possess basal cell carcinoma and squamous cell carcinoma-like features. Using computational tools, organoids, and spatial tools, we show that LY6D+ basosquamous cells represent a persister population lying on a central node along the skin lineage-associated spectrum of epithelial states with local environmental and applied therapies determining the kinetics of accumulation. Surprisingly, LY6D+ basosquamous populations exist in many epithelial tumors, such as pancreatic adenocarcinomas, which have poor outcomes. Overall, our results identify the resistant LY6D+ basosquamous population as an important clinical target and suggest strategies for future therapeutic approaches to target them.

  View details for DOI 10.1038/s41467-022-35020-y

  View details for PubMedID 36473848

  View details for PubMedCentralID PMC9726704

• Development of a novel MEK inhibitor, NFX-179, as a chemoprevention agent for squamous cell carcinoma Sarin, K. Y., Kincaid, J., Sell, B., Shahryari, J., Duncton, M. J., Morefield, E., Sun, W., Chavez-Chiang, O., Plotkin, S. R., Kochendoerfer, G. G., Fenn, P., Powala, C., Tsai, K. Y. AMER ASSOC CANCER RESEARCH. 2022

  View details for Web of Science ID 000896894200022

• Sociodemographic disparities in patch testing for commercially insured patients with dermatitis: A retrospective analysis of administrative claims data JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Qian, M. F., Li, S., Honari, G., Sarin, K. Y., Chen, J. K. 2022; 87 (6): 1411-1413

  View details for DOI 10.1016/j.jaad.2022.08.042

  View details for Web of Science ID 000927902100013

• Development of a novel MEK inhibitor, NFX-179, as a chemoprevention agent for squamous cell carcinoma. Sarin, K. Y., Kincaid, J., Sell, B., Shahryari, J., Duncton, M. J., Morefield, E., Sun, W., Chavez-Chiang, O., Plotkin, S. R., Kochendoerfer, G. G., Fenn, P., Powala, C., Tsai, K. Y. AMER ASSOC CANCER RESEARCH. 2022

  View details for Web of Science ID 000920538200043

• ERK2 MAP kinase regulates SUFU binding by multisite phosphorylation of GLI1. Life science alliance Bardwell, A. J., Wu, B., Sarin, K. Y., Waterman, M. L., Atwood, S. X., Bardwell, L. 2022; 5 (11)

  Abstract

  Crosstalk between the Hedgehog and MAPK signaling pathways occurs in several types of cancer and contributes to clinical resistance to Hedgehog pathway inhibitors. Here we show that MAP kinase-mediated phosphorylation weakens the binding of the GLI1 transcription factor to its negative regulator SUFU. ERK2 phosphorylates GLI1 on three evolutionarily conserved target sites (S102, S116, and S130) located near the high-affinity binding site for SUFU; these phosphorylations cooperate to weaken the affinity of GLI1-SUFU binding by over 25-fold. Phosphorylation of any one, or even any two, of the three sites does not result in the level of SUFU release seen when all three sites are phosphorylated. Tumor-derived mutations in R100 and S105, residues bordering S102, also diminish SUFU binding, collectively defining a novel evolutionarily conserved SUFU affinity-modulating region. In cultured mammalian cells, GLI1 variants containing phosphomimetic substitutions of S102, S116, and S130 displayed an increased ability to drive transcription. We conclude that multisite phosphorylation of GLI1 by ERK2 or other MAP kinases weakens GLI1-SUFU binding, thereby facilitating GLI1 activation and contributing to both physiological and pathological crosstalk.

  View details for DOI 10.26508/lsa.202101353

  View details for PubMedID 35831023

• Assessment of Comorbidities Associated With Allergic Contact Dermatitis in the United States: A Retrospective Claims-Based Study. Dermatitis : contact, atopic, occupational, drug Hua, V. J., Li, S., Qian, M. F., Honari, G., Sarin, K. Y., Chen, J. K. 2022

  Abstract

  BACKGROUND: Allergic contact dermatitis (ACD) is a common dermatologic disease. Patch testing remains the criterion standard for diagnosis. In clinical practice, avoidance may be limited by patient occupation or noncompliance, the pervasive nature of the culprit agent, or barriers to expert care because of socioeconomic, cultural, or geographic factors. Thus, ACD is frequently chronic and/or recurrent; however, the comorbidities associated with ACD are not well characterized.OBJECTIVE: The aim of the study is to identify associations between ACD and psychiatric, sleep health, cardiovascular, and infectious conditions.METHODS: In this study, we used a large US claims database to identify comorbidities associated with ACD diagnosed after patch testing, including psychiatric, sleep health, cardiovascular, and infectious conditions. We also stratified these associations by chronicity of disease.RESULTS: We identified associations between ACD and psychiatric, sleep-related, cardiovascular, and infectious comorbidities. We also found that more chronic ACD was associated with more infectious comorbidities. All of these associations remained significant on further subanalysis when patients with AD and venous stasis were excluded.CONCLUSIONS: Allergic contact dermatitis is associated with multiple comorbidities. Further study is required to corroborate these findings, determine causality, and to explore the impact of possible interventions in the workup and management of this common and often debilitating disease.

  View details for DOI 10.1097/DER.0000000000000964

  View details for PubMedID 36255394

• C5a and C5aR is prominently associated with tunnels in severe hidradenitis suppurativa Li, C., Dunlap, C., Zhao, B., Kilgour, J., Ebsworth, K., Staehr, P., Charo, I., Schall, T., Sarin, K., Sullivan, K. MOSBY-ELSEVIER. 2022: AB147

  View details for Web of Science ID 000891793200581

• Sociodemographic disparities in patch testing for commercially insured dermatitis patients: a retrospective analysis of administrative claims data. Journal of the American Academy of Dermatology Qian, M. F., Li, S., Honari, G., Sarin, K. Y., Chen, J. K. 2022

  View details for DOI 10.1016/j.jaad.2022.08.041

  View details for PubMedID 36041554

• Neurofibromatosis Type 1 and Risk of Skin Cancer. JAMA dermatology Trinh, P., Li, S., Sarin, K. Y. 2022

  View details for DOI 10.1001/jamadermatol.2022.3083

  View details for PubMedID 36001333

• Flexible method for generating needle-shaped beams and its application in optical coherence tomography. Optica Zhao, J., Winetraub, Y., DU, L., VAN Vleck, A., Ichimura, K., Huang, C., AAsI, S. Z., Sarin, K. Y., DE LA Zerda, A. 2022; 9 (8): 859-867

  Abstract

  Needle-shaped beams (NBs) featuring a long depth-of-focus (DOF) can drastically improve the resolution of microscopy systems. However, thus far, the implementation of a specific NB has been onerous due to the lack of a common, flexible generation method. Here we develop a spatially multiplexed phase pattern that creates many axially closely spaced foci as a universal platform for customizing various NBs, allowing flexible manipulations of beam length and diameter, uniform axial intensity, and sub-diffraction-limit beams. NBs designed via this method successfully extended the DOF of our optical coherence tomography (OCT) system. It revealed clear individual epidermal cells of the entire human epidermis, fine structures of human dermal-epidermal junction in a large depth range, and a high-resolution dynamic heartbeat of alive Drosophila larvae.

  View details for DOI 10.1364/optica.456894

  View details for PubMedID 37283722

  View details for PubMedCentralID PMC10243785

• Tuberous sclerosis and risk of skin cancer: a nationwide cohort study in the United States. Journal of the American Academy of Dermatology Trinh, P., Li, S., Sarin, K. Y. 2022

  View details for DOI 10.1016/j.jaad.2022.06.029

  View details for PubMedID 35728719

• Single-cell analysis of human basal cell carcinoma reveals novel regulators of tumor growth and the tumor microenvironment. Science advances Guerrero-Juarez, C. F., Lee, G. H., Liu, Y., Wang, S., Karikomi, M., Sha, Y., Chow, R. Y., Nguyen, T. T., Iglesias, V. S., Aasi, S., Drummond, M. L., Nie, Q., Sarin, K., Atwood, S. X. 2022; 8 (23): eabm7981

  Abstract

  How basal cell carcinoma (BCC) interacts with its tumor microenvironment to promote growth is unclear. We use singe-cell RNA sequencing to define the human BCC ecosystem and discriminate between normal and malignant epithelial cells. We identify spatial biomarkers of tumors and their surrounding stroma that reinforce the heterogeneity of each tissue type. Combining pseudotime, RNA velocity-PAGA, cellular entropy, and regulon analysis in stromal cells reveals a cancer-specific rewiring of fibroblasts, where STAT1, TGF-beta, and inflammatory signals induce a noncanonical WNT5A program that maintains the stromal inflammatory state. Cell-cell communication modeling suggests that tumors respond to the sudden burst of fibroblast-specific inflammatory signaling pathways by producing heat shock proteins, whose expression we validated in situ. Last, dose-dependent treatment with an HSP70 inhibitor suppresses in vitro vismodegib-resistant BCC cell growth, Hedgehog signaling, and in vivo tumor growth in a BCC mouse model, validating HSP70's essential role in tumor growth and reinforcing the critical nature of tumor microenvironment cross-talk in BCC progression.

  View details for DOI 10.1126/sciadv.abm7981

  View details for PubMedID 35687691

• Development of a Core Outcome Set for Basal Cell Carcinoma (BCC), Including Low-Risk and Advanced Tumors. Journal of the American Academy of Dermatology Schlessinger, D. I., Reynolds, K. A., Dirr, M. A., Ibrahim, S. A., Yanes, A. F., Lazaroff, J. M., Godinez-Puig, V., Chen, B. R., Kurta, A. O., Cotseones, J. K., Chiren, S. G., Furlan, K. C., Iyengar, S., Behshad, R., DeHoratius, D. M., Denes, P., Drucker, A. M., Dzubow, L. M., Etzkorn, J. R., Harwood, C. A., Kim, J. Y., Lawrence, N., Lee, E. H., Lissner, G. S., Marghoob, A. A., Matin, R. N., Mattox, A. R., Mittal, B. B., Thomas, J. R., Zhou, X. A., Zloty, D., Schmitt, J., Kirkham, J. J., Armstrong, A. W., Basset-Seguin, N., Billingsley, E. M., Bordeaux, J. S., Brewer, J., Brown, M., Brown, M., Collins, S. A., Fargnoli, M. C., De Azevedo, S. J., Dummer, R., Eggermont, A., Goldman, G. D., Haedersdal, M., Hale, E., Hanlon, A., Harms, K. L., Huang, C. C., Hurst, E. A., In, G. K., Kelleners-Smeets, N., Kheterpal, M., Leshin, B., Mcdonald, M., Miller, S. J., Miller, A., Mostow, E. N., Trakatelli, M., Nehal, K. S., Ratner, D., Rogers, H., Sarin, K. Y., Soon, S. L., Stasko, T., Storrs, P. A., Tagliaferri, L., Vidimos, A. T., Wong, S. L., Yu, S. S., Zalaudek, I., Zeitouni, N. C., Zitelli, J. A., Poon, E., Sobanko, J. F., Cartee, T. V., Maher, I. A., Alam, M. 2022

  Abstract

  BACKGROUND: There is variation in the outcomes reported in clinical studies of basal cell carcinoma (BCC). This can prevent effective meta-analyses to answer important clinical questions.OBJECTIVE: To identify a recommended minimum set of core outcomes for BCC clinical trials.METHODS: Patient and professional Delphi process to cull a long-list, culminating in a consensus meeting. To be provisionally accepted, outcomes needed to be deemed 'important' (score: 7-9, of maximum of 9) by 70% of each stakeholder group.RESULTS: 235 candidate outcomes identified via a systematic literature review and survey of key stakeholders were reduced to 74 that were rated by 100 health care professionals and patients in two Delphi rounds. 27 outcomes were provisionally accepted. The final core set of 5 agreed-upon outcomes after the consensus meeting was: complete response; persistent or serious adverse events; recurrence-free survival; quality of life; and patient satisfaction, including with cosmetic outcome.LIMITATIONS: English-speaking patients and professionals rated outcomes extracted from English-language studies.CONCLUSIONS: A core outcome set (COS) for basal cell carcinoma has been developed. Use of relevant measures may improve the utility of clinical research and the quality of therapeutic guidance available to clinicians.

  View details for DOI 10.1016/j.jaad.2022.04.059

  View details for PubMedID 35551965

• Partnering with a senior living community to optimize teledermatology via full body skin screening during the COVID-19 pandemic: a pilot program Skin Health and Disease Trinh, P., Yekrang, K., Phung, M., Pugliese, S., Chang, A., Bailey, E., Ko, J., Sarin, K. 2022

  View details for DOI 10.1002/ski2.141

• Flexible method for generating needle-shaped beams and its application in optical coherence tomography Optica Zhao, J., Winetraub, Y., Du, L., Vleck, A. V., Ichimura, K., Huang, C., Aasi, S. Z., Sarin, K. Y., de la Zerda, A. 2022; 9 (8): 859-867

  View details for DOI 10.1364/optica.456894

• Treatment of Cutaneous Squamous Cell Carcinoma With the Topical Histone Deacetylase Inhibitor Remetinostat. JAMA dermatology Kilgour, J. M., Shah, A., Eichstadt, S., Bailey, I., Aasi, S. Z., Sarin, K. Y. 2021

  View details for DOI 10.1001/jamadermatol.2021.4549

  View details for PubMedID 34787644

• Characterization of comorbidity heterogeneity among 13,667 patients with hidradenitis suppurativa. JCI insight Hua, V. J., Kilgour, J. M., Cho, H. G., Li, S., Sarin, K. Y. 2021

  Abstract

  Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disorder characterized by recurrent abscesses in the groin and flexural areas. HS is associated with a wide range of comorbidities that complicate the disease course. Although these comorbidities have been well-described, it remains unclear how these comorbidities co-associate and whether comorbidity profiles affect disease trajectory. In addition, it is unknown how comorbidity associations are modulated by race and gender. In this comprehensive analysis of 77 million patients in a large U.S. population-based cohort, we examine co-association patterns among HS comorbidities and identify clinically relevant phenotypic subtypes within HS. We demonstrate that these subtypes not only differ among races, but also influence clinical outcomes as measured by HS-related emergency department (ED) visits and cellulitis. Taken together, our findings provide key insights that elucidate the unique disease trajectories experienced by HS patients, and equip clinicians with a novel framework for risk stratification and improved targeted care in HS.

  View details for DOI 10.1172/jci.insight.151872

  View details for PubMedID 34546979

• Transcriptomic Repositioning Analysis Identifies mTOR Inhibitor as Potential Therapy for Epidermolysis Bullosa Simplex. The Journal of investigative dermatology Lee, G. H., Lekwuttikarn, R., Tafoya, E., Martin, M., Sarin, K. Y., Teng, J. M. 2021

  Abstract

  Expression-based systematic drug repositioning has been explored to predict novel treatments for a number of skin disorders. Here, we utilize this approach to identify, to our knowledge, previously unreported therapies for epidermolysis bullosa simplex (EBS). RNA sequencing analysis was performed on skin biopsies of acute blisters (<1 week) (n=9) and non-blistered epidermis (n=11) obtained from 11 EBS patients. Transcriptomic analysis of blistered epidermis in EBS patients revealed a set of 1276 genes dysregulated in EBS blisters. The IL-6, IL-8, and IL-10 pathways were upregulated in epidermis from EBS. Consistent with this, predicted upstream regulators included TNF-alpha, IL-1beta, IL2, IL-6, PI3K, and mTOR. The 1276 gene EBS blister signature was integrated with molecular signatures from cell lines treated with 2423 drugs using the ConnectivityMap CLUE platform. mTOR inhibitors and PI3K inhibitors most opposed the EBS signature. To determine if mTOR inhibitors could be used clinically in EBS, we conducted an independent pilot study of 2 patients with EBS treated with topical sirolimus for painful plantar keratoderma due to chronic blistering. Both individuals experienced marked clinical improvement and notable reduction of keratoderma. In summary, a computational drug repositioning analysis successfully identified, to our knowledge, previously unreported targets in the treatment of EBS.

  View details for DOI 10.1016/j.jid.2021.07.170

  View details for PubMedID 34536484

• Phase II Open-Label, Single-Arm Trial to Investigate the Efficacy and Safety of Topical Remetinostat Gel in Patients with Basal Cell Carcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research Kilgour, J. M., Shah, A., Urman, N. M., Eichstadt, S., Do, H. N., Bailey, I., Mirza, A., Li, S., Oro, A. E., Aasi, S. Z., Sarin, K. Y. 2021

  Abstract

  PURPOSE: The mainstay of treatment for basal cell carcinoma (BCC) is surgical excision, which can result in significant associated morbidity, particularly for patients with recurrent tumors. We previously conducted a drug repositioning screen using molecular data from human BCCs and identified histone deacetylase (HDAC) inhibitors as a potential treatment for BCC. Here we conduct the first proof-of-principle study of a topical pan-HDAC inhibitor, remetinostat, in human BCC.PATIENTS AND METHODS: We conducted a phase II, open-label, single-arm, single-institution trial of a topical HDAC inhibitor. Participants with at least one BCC were recruited. All participants applied 1% remetinostat gel three times daily for 6 weeks, with measurements of tumor diameter conducted at baseline and week 8. Surgical excision of the remaining tumor was conducted at the end of the study and microscopic evaluation was performed.RESULTS: Thirty-three per-protocol tumors from 25 participants were included in the analysis. The overall response rate, defined as the proportion of tumors achieving more than 30% decrease in the longest diameter from baseline to week 8, was 69.7% [90% confidence interval (CI), 54%-82.5%]. On pathologic examination, 54.8% of tumors demonstrated complete resolution. Pharmacodynamic analysis demonstrated similar levels of acetylated histone H3 in skin tissue before and after treatment, however, phosphorylation was increased. No systemic adverse events were reported.CONCLUSIONS: The HDAC inhibitor remetinostat is a well-tolerated and effective topical treatment for reducing BCC disease burden in a clinically significant manner. This provides in-human validation of HDAC inhibitors as a therapy for BCC.

  View details for DOI 10.1158/1078-0432.CCR-21-0560

  View details for PubMedID 34362809

• Review of the Molecular Genetics of Basal Cell Carcinoma; Inherited Susceptibility, Somatic Mutations, and Targeted Therapeutics. Cancers Kilgour, J. M., Jia, J. L., Sarin, K. Y. 2021; 13 (15)

  Abstract

  Basal cell carcinoma (BCC) is a significant public health concern, with more than 3 million cases occurring each year in the United States, and with an increasing incidence. The molecular basis of BCC is complex, involving an interplay of inherited genetic susceptibility, including single nucleotide polymorphisms and genetic syndromes, and sporadic somatic mutations, often induced by carcinogenic exposure to UV radiation. This review outlines the currently known germline and somatic mutations implicated in the pathogenesis of BCC, including the key molecular pathways affected by these mutations, which drive oncogenesis. With advances in next generation sequencing and our understanding of the molecular genetics of BCC, established and emerging targeted therapeutics are offering new avenues for the non-surgical treatment of BCC. These agents, including Hedgehog pathway inhibitors, immune modulators, and histone deacetylase inhibitors, will also be discussed.

  View details for DOI 10.3390/cancers13153870

  View details for PubMedID 34359772

• Status and Recommendations for Incorporating Biomarkers for Cutaneous Neurofibromas into Clinical Research. Neurology Wallis, D., Stemmer-Rachamimov, A., Adsit, S., Korf, B., Pichard, D., Blakeley, J., Sarin, K. Y., REiNS International Collaboration 2021

  Abstract

  OBJECTIVE: To summarize existing biomarker data for cutaneous neurofibroma (cNF) and inform the incorporation of biomarkers into clinical trial design for cNFs. METHODS: The cNF working group, a subgroup of the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) consortium, was formed to review and inform clinical trial design for cNFs. Between June 2018 and February 2020, the cNF working group performed a review of existing data on genetic biomarkers for cNFs in the setting of Neurofibromatosis Type 1 (NF1). We also reviewed criteria for successful biomarker application in the clinic. The group then met during a series of meetings to develop a consensus report.RESULTS: Our systematic literature review of existing data revealed a lack of validated biomarkers for cNFs. In our report, we summarize the existing signaling, genomic, transcriptomic, histopathologic and proteomic data relevant to cNF. Finally, we make recommendations for incorporating exploratory aims for predictive biomarkers in clinical trials through biobanking samples.CONCLUSION: These recommendations are intended to provide both researchers and clinicians with best practices for clinical trial design to aid in the identification of clinically validated biomarkers for cNF.

  View details for DOI 10.1212/WNL.0000000000012426

  View details for PubMedID 34230199

• Hidradenitis suppurativa in patients of color is associated with increased disease severity and healthcare utilization: A retrospective analysis of 2 U.S. cohorts. JAAD international Kilgour, J. M., Li, S., Sarin, K. Y. 2021; 3: 42-52

  Abstract

  Background: Hidradenitis suppurativa (HS) is known to disproportionately affect patients of color; however, there is a paucity of evidence on how its disease profile varies between races and ethnic groups.Objective: Explore potential race-dependent differences in the disease profile of HS.Methods: A retrospective analysis was conducted on HS patients at Stanford Hospital and Clinics. Data were compared in terms of demographics, disease severity, and healthcare utilization between races in adults identified to have at least 2 encounters coded for HS. Validation was conducted using Optum's de-identified Clinformatics Data Mart Database of national insurance claims.Results: Our cohorts consisted of 939 HS patients seen at Stanford and 13,885 HS patients taken from the national dataset. Black and Hispanic patients had greater healthcare utilization compared to White patients. In addition, Hispanic patients at our institution also had significantly increased disease severity compared to their White counterparts (chi 2 P=.009). Hispanic patients entered tertiary care at an earlier age (Stanford mean: 30.8years for Hispanics vs 38.7 for Whites; P<.001), while Black patients entered later (Stanford mean: 39.6years).Limitations: These cohorts may not be representative of the entire HS patient population.Conclusion: Our findings suggest that patients of color may have greater healthcare utilization and disease severity compared to other groups.

  View details for DOI 10.1016/j.jdin.2021.01.007

  View details for PubMedID 34409370

• Automated detection of skin reactions in epicutaneous patch testing using machine learning. The British journal of dermatology Chan, W. H., Srivastava, R., Damaraju, N., Do, H., Burnett, G., MacFarlane, J., Xie, S. M., Chen, J. K., Honari, G., Sarin, K. Y. 2021

  Abstract

  Patch testing is the diagnostic gold standard to identify causes of allergic contact dermatitis (ACD); however, the paucity of specialized patch testing clinics along with the need for multiple clinic visits can be burdensome for patients and healthcare systems. Automated classification of allergic reactions from photographs offers the opportunity to reduce patient, physician, and clinic time and improve access to care.

  View details for DOI 10.1111/bjd.20141

  View details for PubMedID 33829497

• Direct-to-Consumer Genetic Risk Scoring for Melanoma Improves Adherence to Sun-Protective Behaviors Among Increased-Risk Groups: Results from a Prospective U.S. Cohort Study. Journal of the American Academy of Dermatology Hu, X. n., Kilgour, J. M., Fogel, A. L., Jia, J. L., Jaju, P. D., Tang, J. Y., Sarin, K. Y. 2021

  View details for DOI 10.1016/j.jaad.2021.01.042

  View details for PubMedID 33476728

• Prevalence of Potentially Allergenic Ingredients in Products Labeled for Eczema Care. Journal of the American Academy of Dermatology Schwartz, B. L., Honari, G., Chiou, A. S., Ko, J., Sarin, K. Y., Chen, J. K. 2021

  View details for DOI 10.1016/j.jaad.2021.05.038

  View details for PubMedID 34058279

• Journal attitudes and outcomes of preprints in dermatology. The British journal of dermatology Jia, J. L., Hua, V. J., Mills, D. E., Sarin, K. Y. 2021

  Abstract

  The use of preprints, manuscripts that can be uploaded to a public server and made almost immediately available for public dissemination without peer review, is becoming increasingly common.1 Preprint servers are not typically associated with established peer-reviewed journals and often operate independently. Proponents of preprints point toward improved rapid dissemination of results and opportunities for crowdsourced feedback before submission to peer-reviewed journals.1 Conversely, inconsistent upload criteria among preprint servers (such as lack of guidance for reporting conflict of interest or image manipulation),1 and the risk for widespread discourse of non-peer reviewed results by news media may impinge on research integrity.2 As members of the public may not understand the difference between preprints and traditionally peer-reviewed articles, preprints have the potential to cause widespread confusion and mistrust.2 Use of preprints may also make publication of results in traditional journals more difficult, as the results may be perceived to be less novel. Despite controversy, the number of preprints continue to rise.3 There is limited understanding of how dermatology journals view and consider preprints. In this study, we explore dermatology journal policies toward the submission of preprint articles for publication, and corresponding publication outcomes of dermatology articles previously uploaded to a large clinically oriented preprint server.

  View details for DOI 10.1111/bjd.20065

  View details for PubMedID 33742455

• Loss-of-Function Variants in the Tumor Suppressor Gene PTPN14 confer increased Cancer Risk. Cancer research Olafsdottir, T. n., Stacey, S. N., Sveinbjornsson, G. n., Thorleifsson, G. n., Norland, K. n., Sigurgeirsson, B. n., Thorisdottir, K. n., Kristjansson, A. K., Tryggvadottir, L. n., Sarin, K. Y., Benediktsson, R. n., Jonasson, J. G., Sigurdsson, A. n., Jonasdottir, A. n., Kristmundsdottir, S. n., Jonsson, H. n., Gylfason, A. n., Oddsson, A. n., Fridriksdottir, R. n., Gudjonsson, S. A., Zink, F. n., Lund, S. H., Rognvaldsson, S. n., Melsted, P. n., Steinthorsdottir, V. n., Gudmundsson, J. n., Mikaelsdottir, E. n., Olason, P. I., Stefansdottir, L. n., Eggertsson, H. P., Halldorsson, B. V., Thorsteinsdottir, U. n., Agustsson, T. T., Olafsson, K. n., Olafsson, J. H., Sulem, P. n., Rafnar, T. n., Gudbjartsson, D. F., Stefansson, K. n. 2021

  Abstract

  The success of genome-wide association studies (GWAS) in identifying common, low-penetrance variant-cancer associations for the past decade is undisputed. However, discovering additional high-penetrance cancer mutations in unknown cancer predisposing genes requires detection of variant-cancer association of ultra-rare coding variants. Consequently, large-scale next generation sequence data with associated phenotype information are needed. Here we used genotype data on 166,281 Icelanders, of which 49,708 were whole-genome sequenced, and 408,595 individuals from the UK Biobank, of which 41,147 were whole-exome sequenced, to test for association between loss-of-function burden in autosomal genes and basal cell carcinoma (BCC), the most common cancer in Caucasians. 25,205 BCC cases and 683,058 controls were tested. Rare germline loss-of-function variants in PTPN14 conferred substantial risks of BCC (OR=8.0, P=1.9×10-12), with a quarter of carriers getting BCC before age 70 and over half in their lifetime. Furthermore, common variants at the PTPN14 locus were associated with BCC, suggesting PTPN14 as a new, high-impact BCC predisposition gene. A follow-up investigation of 24 cancers and three benign tumor types showed that PTPN14 loss-of-function variants are associated with high risk of cervical cancer (OR=12.7, P=1.6×10-4) and low age at diagnosis. Our findings, using power-increasing methods with high quality rare variant genotypes, highlight future prospects for new discoveries on carcinogenesis.

  View details for DOI 10.1158/0008-5472.CAN-20-3065

  View details for PubMedID 33602785

• Crowdfunding for the treatment of cutaneous malignancies: Trends, correlates, and money raised Jia, J. L., Mills, D., Sarin, K. Y. MOSBY-ELSEVIER. 2020: AB107

  View details for Web of Science ID 000598634300427

• Ways to Improve Care for LGBT Patients in Dermatology Clinics. Dermatologic clinics Jia, J. L., Polin, D. J., Sarin, K. Y. 2020; 38 (2): 269–76

  Abstract

  Lesbian, Gay, Bisexual, and Transgender (LGBT) patients face significant dermatologic health disparities. LGBT patients are often discriminated against, refused healthcare, or otherwise have negative healthcare experiences that may deter future utilization of professional care. While a number of factors may mitigate these negative experiences, the present article focuses on improving organizational and institutional drivers specific to individual dermatology clinics. Clinic workflow and operations, emerging technologies and EHRs, clinic culture, clinic environment and resource availability, and provider and staff education are all characteristics of healthcare clinics that can be improved to better facilitate high-quality dermatologic care for LGBT patients.

  View details for DOI 10.1016/j.det.2019.10.012

  View details for PubMedID 32115137

• Sexual and Gender Minority Curricula Within US Dermatology Residency Programs. JAMA dermatology Jia, J. L., Nord, K. M., Sarin, K. Y., Linos, E., Bailey, E. E. 2020

  View details for DOI 10.1001/jamadermatol.2020.0113

  View details for PubMedID 32186684

• Angular compounding for speckle reduction in optical coherence tomography using geometric image registration algorithm and digital focusing. Scientific reports Zhao, J., Winetraub, Y., Yuan, E., Chan, W. H., Aasi, S. Z., Sarin, K. Y., Zohar, O., de la Zerda, A. 2020; 10 (1): 1893

  Abstract

  Optical coherence tomography (OCT) suffers from speckle noise due to the high spatial coherence of the utilized light source, leading to significant reductions in image quality and diagnostic capabilities. In the past, angular compounding techniques have been applied to suppress speckle noise. However, existing image registration methods usually guarantee pure angular compounding only within a relatively small field of view in the focal region, but produce spatial averaging in the other regions, resulting in resolution loss and image blur. This work develops an image registration model to correctly localize the real-space location of every pixel in an OCT image, for all depths. The registered images captured at different angles are fused into a speckle-reduced composite image. Digital focusing, based on the convolution of the complex OCT images and the conjugate of the point spread function (PSF), is studied to further enhance lateral resolution and contrast. As demonstrated by experiments, angular compounding with our improved image registration techniques and digital focusing, can effectively suppress speckle noise, enhance resolution and contrast, and reveal fine structures in ex-vivo imaged tissue.

  View details for DOI 10.1038/s41598-020-58454-0

  View details for PubMedID 32024946

• Prevalence and risk factors for high frequency basal cell carcinoma in the United States. Journal of the American Academy of Dermatology Chiang, A. n., Solis, D. C., Rogers, H. n., Sohn, G. K., Cho, H. G., Saldanha, G. n., Lapidus, D. n., Li, S. n., Sarin, K. Y., Tang, J. Y. 2020

  View details for DOI 10.1016/j.jaad.2020.07.088

  View details for PubMedID 32735972

• Gamification improves melanoma visual identification among high school students: Results from a randomized study. Pediatric dermatology Jia, J. L., Shen, A. n., Tabata, M. M., Sarin, K. Y. 2020

  Abstract

  Identification of melanoma or worrisome moles is often taught as an important part of routine skin checks. We sought to evaluate the efficacy of gamified education vs. traditional ABCDEs education on melanoma identification and self-confidence in identifying worrisome moles. We report that in our cohort (n = 271), participants randomized to the gamified intervention were more likely to correctly identify melanoma and non-melanoma skin lesions than those randomized to the ABCDE control cohort (74.2% vs 63.5% correct, P < .0001) and perceived confidence in self-identifying worrisome lesions was slightly higher in the gamified group than the traditional group, though the trend was not significant. These novel findings have significant implications on improved ways to educate young patients on the visual identification of melanoma and worrisome moles.

  View details for DOI 10.1111/pde.14158

  View details for PubMedID 32266730

• Fitzpatrick Phototype Disparities in Identification of Cutaneous Malignancies by Google Reverse Image. Journal of the American Academy of Dermatology Jia, J. L., Wang, J. Y., Mills, D. E., Shen, A. n., Sarin, K. Y. 2020

  View details for DOI 10.1016/j.jaad.2020.05.005

  View details for PubMedID 32389713

• A phase 2 double-blinded, placebo-controlled trial of toll-like receptor 7,8,9 antagonist, IMO-8400, in dermatomyositis. Journal of the American Academy of Dermatology Kim, Y. J., Schiopu, E. n., Dankó, K. n., Mozaffar, T. n., Chunduru, S. n., Lees, K. n., Goyal, N. n., Sarazin, J. n., Fiorentino, D. F., Sarin, K. Y. 2020

  View details for DOI 10.1016/j.jaad.2020.07.122

  View details for PubMedID 32781178

• AP-1 and TGFSS cooperativity drives non-canonical Hedgehog signaling in resistant basal cell carcinoma. Nature communications Yao, C. D., Haensel, D., Gaddam, S., Patel, T., Atwood, S. X., Sarin, K. Y., Whitson, R. J., McKellar, S., Shankar, G., Aasi, S., Rieger, K., Oro, A. E. 2020; 11 (1): 5079

  Abstract

  Tumor heterogeneity and lack of knowledge about resistant cell states remain a barrier to targeted cancer therapies. Basal cell carcinomas (BCCs) depend on Hedgehog (Hh)/Gli signaling, but can develop mechanisms of Smoothened (SMO) inhibitor resistance. We previously identified a nuclear myocardin-related transcription factor (nMRTF) resistance pathway that amplifies noncanonical Gli1 activity, but characteristics and drivers of the nMRTF cell state remain unknown. Here, we use single cell RNA-sequencing of patient tumors to identify three prognostic surface markers (LYPD3, TACSTD2, and LY6D) which correlate with nMRTF and resistance to SMO inhibitors. The nMRTF cell state resembles transit-amplifying cells of the hair follicle matrix, with AP-1 and TGFSS cooperativity driving nMRTF activation. JNK/AP-1 signaling commissions chromatin accessibility and Smad3 DNA binding leading to a transcriptional program of RhoGEFs that facilitate nMRTF activity. Importantly, small molecule AP-1 inhibitors selectively target LYPD3+/TACSTD2+/LY6D+ nMRTF human BCCs ex vivo, opening an avenue for improving combinatorial therapies.

  View details for DOI 10.1038/s41467-020-18762-5

  View details for PubMedID 33033234

• Patient Crowdfunding for the Treatment of Cutaneous Malignancies. Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.] Jia, J. L., Mills, D. E., Urman, N. M., Sarin, K. Y. 2020

  View details for DOI 10.1097/DSS.0000000000002866

  View details for PubMedID 33165076

• From Clinical Phenotype to Genotypic Modelling: Incidence and Prevalence of Recessive Dystrophic Epidermolysis Bullosa (RDEB). Clinical, cosmetic and investigational dermatology Eichstadt, S., Tang, J. Y., Solis, D. C., Siprashvili, Z., Marinkovich, M. P., Whitehead, N., Schu, M., Fang, F., Erickson, S. W., Ritchey, M. E., Colao, M., Spratt, K., Shaygan, A., Ahn, M. J., Sarin, K. Y. 2019; 12: 933-942

  Abstract

  Recessive dystrophic epidermolysis bullosa (RDEB) is an inherited genetic disorder characterized by recurrent and chronic open wounds with significant morbidity, impaired quality of life, and early mortality. RDEB patients demonstrate reduction or structural alteration type VII collagen (C7) owing to mutations in the gene COL7A1, the main component of anchoring fibrils (AF) necessary to maintain epidermal-dermal cohesion. While over 700 alterations in COL7A1 have been reported to cause dystrophic epidermolysis bullosa (DEB), which may be inherited in an autosomal dominant (DDEB) or autosomal recessive pattern (RDEB), the incidence and prevalence of RDEB is not well defined. To date, the widely estimated incidence (0.2-6.65 per million births) and prevalence (3.5-20.4 per million people) of RDEB has been primarily characterized by limited analyses of clinical databases or registries.Using a genetic modelling approach, we use whole exome and genome sequencing data to estimate the allele frequency of pathogenic variants. Through the ClinVar and NCBI database of human genome variants and phenotypes, DEB Register, and analyzing premature COL7A1 termination variants we built a model to predict the pathogenicity of previously unclassified variants. We applied the model to publicly available sequences from the Exome Aggregation Consortium (ExAC) and Genome Aggregation Database (gnomAD) and identified variants which were classified as pathogenic for RDEB from which we estimate disease incidence and prevalence.Genetic modelling applied to the whole exome and genome sequencing data resulted in the identification of predicted RDEB pathogenic alleles, from which our estimate of the incidence of RDEB is 95 per million live births, 30 times the 3.05 per million live birth incidence estimated by the National Epidermolysis Bullosa Registry (NEBR). Using a simulation approach, we estimate a mean of approximately 3,850 patients in the US who may benefit from COL7A1-mediated treatments in the US.We conclude that genetic allele frequency estimation may enhance the underdiagnosis of rare genetic diseases generally, and RDEB specifically, which may improve incidence and prevalence estimates of patients who may benefit from treatment.

  View details for DOI 10.2147/CCID.S232547

  View details for PubMedID 31920360

  View details for PubMedCentralID PMC6935313

• A phase 1b, open-label, investigator-initiated, proof-of-concept study of pembrolizumab for advanced basal cell carcinomas Chang, A., Duy Tran, Cannon, J., Li, S., Jeng, M., Rieger, K., Reddy, S., Sarin, K., Colevas, D. MOSBY-ELSEVIER. 2019: AB8

  View details for Web of Science ID 000482195000029

• Hyperhidrosis affects quality of life in hidradenitis suppurativa: a prospective analysis. Journal of the American Academy of Dermatology Hua, V. J., Kuo, K. Y., Cho, H. G., Sarin, K. Y. 2019

  View details for DOI 10.1016/j.jaad.2019.08.046

  View details for PubMedID 31449904

• Response to Clarifying the Current Understanding of Syndromic Basal Cell Carcinomas. The Journal of investigative dermatology Chiang, A., Batra, P., Sarin, K. Y. 2019

  Abstract

  A majority of individuals with BCNS have germline mutations affecting PTCH1, and BCCs that develop in these individuals are highly responsive to Smoothened inhibitors. However, BCCs which develop in minority of BCNS patients with underlying SUFU mutations may be less responsive to Smoothened inhibitors because inactivation of SUFU is downstream of SMO. Development of next-generation HH antagonists that target components downstream of SMO are under development for efficacy in Smoothened inhibitor resistant BCCs and may have efficacy in BCCs with SUFU mutations.

  View details for DOI 10.1016/j.jid.2019.06.139

  View details for PubMedID 31330148

• Loss of Primary Cilia Drives Switching from Hedgehog to Ras/MAPK Pathway in Resistant Basal Cell Carcinoma JOURNAL OF INVESTIGATIVE DERMATOLOGY Kuonen, F., Huskey, N. E., Shankar, G., Jaju, P., Whitson, R. J., Rieger, K. E., Atwood, S. X., Sarin, K. Y., Oro, A. E. 2019; 139 (7): 1439–48

  View details for DOI 10.1016/j.jid.2018.11.035

  View details for Web of Science ID 000472234100017

• Biomarker discovery analysis: Alterations in p14, p16, p53, and BAP1 expression in nevi, cutaneous melanoma, and metastatic melanoma PIGMENT CELL & MELANOMA RESEARCH Sargen, M. R., Cloutier, J. M., Sarin, K. Y., Rieger, K. E., Chu, P., Swetter, S. M., Novoa, R. A. 2019; 32 (3): 474–78

  View details for DOI 10.1111/pcmr.12768

  View details for Web of Science ID 000465607700016

• Alterations of the MEK/ERK, BMP, and Wnt/beta-catenin pathways detected in the blood of individuals with lymphatic malformations PLOS ONE Kim, T., Tafoya, E., Chelliah, M. P., Lekwuttikarn, R., Li, J., Sarin, K. Y., Teng, J. 2019; 14 (4)

  View details for DOI 10.1371/journal.pone.0213872

  View details for Web of Science ID 000463314500013

• Unique Tumor Heterogeneity Within a Single Locally Advanced Basal Cell Carcinoma Resulting in a Partial Response Despite Continuous Vismodegib Treatment DERMATOLOGIC SURGERY Nayyar, P., Chang, A. S., Sarin, K., Ratner, D. 2019; 45 (4): 608–10

  View details for DOI 10.1097/DSS.0000000000001607

  View details for Web of Science ID 000480739500020

  View details for PubMedID 30045109

• Emerging technologies for health information in dermatology: opportunities and drawbacks of web-based searches, social media, mobile applications, and direct-to-consumer genetic testing in patient care SEMINARS IN CUTANEOUS MEDICINE AND SURGERY Jia, J. L., Polin, D. J., Sarin, K. Y. 2019; 38 (1): E57–E63

  View details for DOI 10.12788/j.sder.2019.002

  View details for Web of Science ID 000495364500010

• Pembrolizumab for advanced basal cell carcinoma: An investigator-initiated, proof-of-concept study JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Chang, A. S., Tran, D. C., Cannon, J. D., Li, S., Jeng, M., Patel, R., Van der Bokke, L., Pague, A., Brotherton, R., Rieger, K. E., Satpathy, A. T., Yost, K. E., Reddy, S., Sarin, K., Colevas, A. 2019; 80 (2): 564–66

  View details for DOI 10.1016/j.jaad.2018.08.017

  View details for Web of Science ID 000455473200042

• Loss of primary cilia drives switching from Hedgehog to Ras/MAPK pathway in resistant basal cell carcinoma. The Journal of investigative dermatology Kuonen, F., Huskey, N. E., Shankar, G., Jaju, P., Whitson, R. J., Rieger, K. E., Atwood, S. X., Sarin, K. Y., Oro, A. E. 2019

  Abstract

  Basal cell carcinomas (BCCs) rely on Hedgehog (HH) pathway growth signal amplification by the microtubule-based organelle, the primary cilium. Despite naive tumors responsiveness to Smoothened inhibitors (Smoi), resistance in advanced tumors remains frequent. While the resistant BCCs usually maintain HH pathway activation, squamous cell carcinomas with Ras/MAPK pathway activation also arise, with the molecular basis of tumor type and pathway selection still obscure. Here we identify the primary cilium as a critical determinant controlling tumor pathway switching. Strikingly, Smoi-resistant BCCs possess an increased mutational load in ciliome genes, resulting in reduced primary cilia and HH pathway activation compared to naive or Gorlin patient BCCs. Gene set enrichment analysis of resistant BCCs with a low HH pathway signature reveals increased Ras/MAPK pathway activation. Tissue analysis confirms an inverse relationship between primary cilia presence and Ras/MAPK activation, and primary cilia removal in BCCs potentiates Ras/MAPK pathway activation. Moreover, activating Ras in HH-responsive cell lines confers resistance to both canonical (vismodegib) and non-canonical (aPKC and MRTF inhibitors) HH pathway inhibitors, while conferring sensitivity to MAPK inhibitors. Our results provide insights into BCC treatment and identify the primary cilium as an important lineage gatekeeper, preventing HH to Ras/MAPK pathway switching.

  View details for PubMedID 30707899

• Biomarker discovery analysis: Alterations in p14, p16, p53, and BAP1 expression in nevi, cutaneous melanoma, and metastatic melanoma. Pigment cell & melanoma research Sargen, M. R., Cloutier, J. M., Sarin, K. Y., Rieger, K. E., Chu, P., Swetter, S. M., Novoa, R. A. 2019

  Abstract

  Protein biomarkers for diagnosis and prognosis are currently lacking for melanoma, which predominantly relies on histologic features for diagnosis (cytologic and nuclear pleomorphism, growth pattern) and staging (Breslow depth, ulceration). In many cases, the histology of the primary tumor is an unreliable predictor of tumor behavior, and consequently sentinel lymph node biopsy along with imaging studies are often necessary to predict likelihood of mortality from disease. This article is protected by copyright. All rights reserved.

  View details for PubMedID 30672662

• From Clinical Phenotype to Genotypic Modelling: Incidence and Prevalence of Recessive Dystrophic Epidermolysis Bullosa (RDEB) CLINICAL COSMETIC AND INVESTIGATIONAL DERMATOLOGY Eichstadt, S., Tang, J. Y., Solis, D. C., Siprashvili, Z., Marinkovich, M., Whitehead, N., Schu, M., Fang, F., Erickson, S. W., Ritchey, M. E., Colao, M., Spratt, K., Shaygan, A., Ahn, M. J., Sarin, K. Y. 2019; 12: 933–42

  View details for DOI 10.2147/CCID.S232547

  View details for Web of Science ID 000503975800001

• Assessment of readability and content of patient-initiated google search results for epidermolysis bullosa. Pediatric dermatology Jia, J. L., Nguyen, B. n., Sarin, K. Y. 2019

  Abstract

  Epidermolysis bullosa describes a group of conditions commonly characterized by fragile skin and blistering of the mucosal membranes. Due to the complex and rare nature of the disease, we sought to evaluate the quality and readability of epidermolysis bullosa information available online. Analysis of the top 50 search results on Google demonstrated that information by non-dermatologists was of a lower reading level and more accessible when compared to information by dermatologists, even though dermatologist written information was more likely to be useful and medically comprehensive. There is an increasing need for dermatologists to provide useful and medically comprehensive EB information that is accessible to patients and patient families.

  View details for DOI 10.1111/pde.13975

  View details for PubMedID 31468562

• Comparing Online Engagement and Academic Impact of Dermatology Research: An Altmetric Attention Score and PlumX Metrics Analysis. Journal of the American Academy of Dermatology Jia, J. L., Nguyen, B. n., Mills, D. E., Polin, D. J., Sarin, K. Y. 2019

  View details for DOI 10.1016/j.jaad.2019.12.003

  View details for PubMedID 31836559

• Alterations of the MEK/ERK, BMP, and Wnt/beta-catenin pathways detected in the blood of individuals with lymphatic malformations. PloS one Kim, T., Tafoya, E., Chelliah, M. P., Lekwuttikarn, R., Li, J., Sarin, K. Y., Teng, J. 2019; 14 (4): e0213872

  Abstract

  Lymphatic malformation (LM) is a developmental anomaly of the lymphatic system that may lead to disfigurement, organ dysfunction and recurrent infection. Though several treatment modalities exist, pharmacotherapy is often associated with side effects and recurrence is common following surgical interventions. Moreover, despite the recent discovery of PIK3CA mutations in lymphatic endothelial cells of LM patients, the full spectrum of molecular pathways involved in LM pathogenesis is poorly understood. Here, we performed RNA sequencing on blood samples obtained from ten LM patients and nine healthy subjects and found 421 differentially expressed genes that stratify LM subjects from healthy controls. Using this LM gene signature, we identified novel pathway alterations in LM, such as oxidative phosphorylation, MEK/ERK, bone morphogenetic protein (BMP), and Wnt/beta-catenin pathways, in addition to confirming the known alterations in cell cycle and the PI3K/AKT pathway. Furthermore, we performed computational drug repositioning analysis to predict existing therapies (e.g. sirolimus) and novel classes of drugs for LM. These findings deepen our understanding of LM pathogenesis and may facilitate non-invasive diagnosis, pathway analysis and therapeutic development.

  View details for PubMedID 30947262

• Emerging technologies for health information in dermatology: opportunities and drawbacks of web-based searches, social media, mobile applications, and direct-to-consumer genetic testing in patient care. Seminars in cutaneous medicine and surgery Jia, J. L., Polin, D. J., Sarin, K. Y. 2019; 38 (1): E57–E53

  Abstract

  Emerging technology is fundamentally changing how individuals interact with the health care system. Web-based searches, mobile applications, social media, and directto- consumer genetic testing companies are facilitating information exchange at a higher rate than ever before, creating a macroscopic shift in the mechanisms by which individuals seek health information. The visual nature of skin disease enables individuals to browse, share, and search based on images, adding another dimension to how dermatological information is transferred. These trends carry important implications on user health care behavior, and so it is vital for health care professionals to stay attuned to the morphing characteristics of their patients' health management in order to continue to provide high-quality, patient-centered care.

  View details for PubMedID 31051025

• Early Detection of Adverse Drug Reactions in Social Health Networks: A Natural Language Processing Pipeline for Signal Detection. JMIR public health and surveillance Nikfarjam, A. n., Ransohoff, J. D., Callahan, A. n., Jones, E. n., Loew, B. n., Kwong, B. Y., Sarin, K. Y., Shah, N. H. 2019; 5 (2): e11264

  Abstract

  Adverse drug reactions (ADRs) occur in nearly all patients on chemotherapy, causing morbidity and therapy disruptions. Detection of such ADRs is limited in clinical trials, which are underpowered to detect rare events. Early recognition of ADRs in the postmarketing phase could substantially reduce morbidity and decrease societal costs. Internet community health forums provide a mechanism for individuals to discuss real-time health concerns and can enable computational detection of ADRs.The goal of this study is to identify cutaneous ADR signals in social health networks and compare the frequency and timing of these ADRs to clinical reports in the literature.We present a natural language processing-based, ADR signal-generation pipeline based on patient posts on Internet social health networks. We identified user posts from the Inspire health forums related to two chemotherapy classes: erlotinib, an epidermal growth factor receptor inhibitor, and nivolumab and pembrolizumab, immune checkpoint inhibitors. We extracted mentions of ADRs from unstructured content of patient posts. We then performed population-level association analyses and time-to-detection analyses.Our system detected cutaneous ADRs from patient reports with high precision (0.90) and at frequencies comparable to those documented in the literature but an average of 7 months ahead of their literature reporting. Known ADRs were associated with higher proportional reporting ratios compared to negative controls, demonstrating the robustness of our analyses. Our named entity recognition system achieved a 0.738 microaveraged F-measure in detecting ADR entities, not limited to cutaneous ADRs, in health forum posts. Additionally, we discovered the novel ADR of hypohidrosis reported by 23 patients in erlotinib-related posts; this ADR was absent from 15 years of literature on this medication and we recently reported the finding in a clinical oncology journal.Several hundred million patients report health concerns in social health networks, yet this information is markedly underutilized for pharmacosurveillance. We demonstrated the ability of a natural language processing-based signal-generation pipeline to accurately detect patient reports of ADRs months in advance of literature reporting and the robustness of statistical analyses to validate system detections. Our findings suggest the important contributions that social health network data can play in contributing to more comprehensive and timely pharmacovigilance.

  View details for DOI 10.2196/11264

  View details for PubMedID 31162134

• Clonal replacement of tumor-specific T cells following PD-1 blockade. Nature medicine Yost, K. E., Satpathy, A. T., Wells, D. K., Qi, Y. n., Wang, C. n., Kageyama, R. n., McNamara, K. L., Granja, J. M., Sarin, K. Y., Brown, R. A., Gupta, R. K., Curtis, C. n., Bucktrout, S. L., Davis, M. M., Chang, A. L., Chang, H. Y. 2019

  Abstract

  Immunotherapies that block inhibitory checkpoint receptors on T cells have transformed the clinical care of patients with cancer1. However, whether the T cell response to checkpoint blockade relies on reinvigoration of pre-existing tumor-infiltrating lymphocytes or on recruitment of novel T cells remains unclear2-4. Here we performed paired single-cell RNA and T cell receptor sequencing on 79,046 cells from site-matched tumors from patients with basal or squamous cell carcinoma before and after anti-PD-1 therapy. Tracking T cell receptor clones and transcriptional phenotypes revealed coupling of tumor recognition, clonal expansion and T cell dysfunction marked by clonal expansion of CD8+CD39+ T cells, which co-expressed markers of chronic T cell activation and exhaustion. However, the expansion of T cell clones did not derive from pre-existing tumor-infiltrating T lymphocytes; instead, the expanded clones consisted of novel clonotypes that had not previously been observed in the same tumor. Clonal replacement of T cells was preferentially observed in exhausted CD8+ T cells and evident in patients with basal or squamous cell carcinoma. These results demonstrate that pre-existing tumor-specific T cells may have limited reinvigoration capacity, and that the T cell response to checkpoint blockade derives from a distinct repertoire of T cell clones that may have just recently entered the tumor.

  View details for DOI 10.1038/s41591-019-0522-3

  View details for PubMedID 31359002

• Topical Itraconazole for the Treatment of Basal Cell Carcinoma in Patients With Basal Cell Nevus Syndrome or High-Frequency Basal Cell Carcinomas: A Phase 2, Open-Label, Placebo-Controlled Trial. JAMA dermatology Sohn, G. K., Kwon, G. P., Bailey-Healy, I. n., Mirza, A. n., Sarin, K. n., Oro, A. n., Tang, J. Y. 2019

  View details for DOI 10.1001/jamadermatol.2019.1541

  View details for PubMedID 31339515

• A Subset of Mesotheliomas With Improved Survival Occurring in Carriers of BAP1 and Other Germline Mutations JOURNAL OF CLINICAL ONCOLOGY Pastorino, S., Yoshikawa, Y., Pass, H. I., Emi, M., Nasu, M., Pagano, I., Takinishi, Y., Yamamoto, R., Minaai, M., Hashimoto-Tamaoki, T., Ohmuraya, M., Goto, K., Goparaju, C., Sarin, K. Y., Tanji, M., Bononi, A., Napolitano, A., Gaudino, G., Hesdorffer, M., Yang, H., Carbone, M. 2018; 36 (35): 3485-+

  View details for DOI 10.1200/JCO.2018.79.0352

  View details for Web of Science ID 000454367700007

• TGF beta, Fibronectin and Integrin alpha 5 beta 1 Promote Invasion in Basal Cell Carcinoma JOURNAL OF INVESTIGATIVE DERMATOLOGY Kuonen, F., Surbeck, I., Sarin, K. Y., Dontenwill, M., Ruegg, C., Gilliet, M., Oro, A. E., Gaide, O. 2018; 138 (11): 2432-2442

  View details for DOI 10.1016/j.jid.2018.04.029

  View details for Web of Science ID 000447794000024

• A Subset of Mesotheliomas With Improved Survival Occurring in Carriers of BAP1 and Other Germline Mutations. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Pastorino, S., Yoshikawa, Y., Pass, H. I., Emi, M., Nasu, M., Pagano, I., Takinishi, Y., Yamamoto, R., Minaai, M., Hashimoto-Tamaoki, T., Ohmuraya, M., Goto, K., Goparaju, C., Sarin, K. Y., Tanji, M., Bononi, A., Napolitano, A., Gaudino, G., Hesdorffer, M., Yang, H., Carbone, M. 2018: JCO2018790352

  Abstract

  PURPOSE: We hypothesized that four criteria could help identify malignant mesotheliomas (MMs) most likely linked to germline mutations of BAP1 or of other genes: family history of MM, BAP1-associated cancers, or multiple malignancies; or age younger than 50 years.PATIENTS AND METHODS: Over the course of 7 years, 79 patients with MM met the four criteria; 22 of the 79 (28%) reported possible asbestos exposure. They were screened for germline BAP1 mutations by Sanger sequencing and by targeted next-generation sequencing (tNGS) for germline mutations in 55 additional cancer-linked genes. Deleterious mutations detected by tNGS were validated by Sanger sequencing.RESULTS: Of the 79 patients, 43 (16 probands and 27 relatives) had deleterious germline BAP1 mutations. The median age at diagnosis was 54 years and median survival was 5 years. Among the remaining 36 patients with no BAP1 mutation, median age at diagnosis was 45 years, median survival was 9 years, and 12 had deleterious mutations of additional genes linked to cancer. When compared with patients with MMs in the SEER cohort, median age at diagnosis (72 years), median survival for all MM stages (8 months), and stage I (11 months) were significantly different from the 79 patients with MM in the current study ( P < .0001).CONCLUSION: We provide criteria that help identify a subset of patients with MM who had significantly improved survival. Most of these patients were not aware of asbestos exposure and carried either pathogenic germline mutations of BAP1 or of additional genes linked to cancer, some of which may have targeted-therapy options. These patients and their relatives are susceptible to development of additional cancers; therefore, genetic counseling and cancer screening should be considered.

  View details for PubMedID 30376426

• Automated Classification of Skin Lesions: From Pixels to Practice. The Journal of investigative dermatology Narla, A., Kuprel, B., Sarin, K., Novoa, R., Ko, J. 2018; 138 (10): 2108–10

  Abstract

  The letters "Interpretation of the Outputs of Deep Learning Model trained with Skin Cancer Dataset" and "Automated Dermatological Diagnosis: Hype or Reality?" highlight the opportunities, hurdles, and possible pitfalls with the development of tools that allow for automated skin lesion classification. The potential clinical impact of these advances relies on their scalability, accuracy, and generalizability across a range of diagnostic scenarios.

  View details for PubMedID 30244720

• Automated Classification of Skin Lesions: From Pixels to Practice JOURNAL OF INVESTIGATIVE DERMATOLOGY Narla, A., Kuprel, B., Sarin, K., Novoa, R., Ko, J. 2018; 138 (10): 2108-2110

  View details for DOI 10.1016/j.jid.2018.06.175

  View details for Web of Science ID 000445104700008

• Association of multiple primary melanomas with malignancy risk: a population-based analysis of the Surveillance, Epidemiology, and End Results Program database from 1973-2014. Journal of the American Academy of Dermatology Cai, E. D., Swetter, S. M., Sarin, K. Y. 2018

  Abstract

  BACKGROUND: Genetic and environmental risk factors have been associated with the development of multiple primary melanomas (MPM). We hypothesized that individuals with MPM may have increased predisposition to developing internal malignancies.OBJECTIVE: To identify the risk of subsequent malignancies in MPM patients.METHODS: Multiple primary standardized incidence ratios were analyzed for individuals with ≥1, ≥2 and ≥3 primary melanomas (PM) in the SEER database from 1973-2014.RESULTS: 223,799 individuals with ≥1, 19,709 with ≥2 and 3,995 with ≥3 PM were identified. Risks of subsequent internal malignancy increased with number of PM, with observed to expected (O/E) ratios of 0.99, 1.14, and 1.23 (p<0.05) for patients with at least one, two and three PM respectively. Internal malignancy was higher in younger MPM patients and those with superficial spreading melanoma. The most common malignancies amongst MPM patients include breast, prostate, thyroid, soft tissue, brain, kidney, non-Hodgkin's lymphoma, and chronic lymphocytic leukemia. Risk of subsequent cutaneous melanoma increased with O/E ratios of 8.09, to 22.52, to 41.03 (p<0.05) respectively.LIMITATIONS: SEER records limited information about pigmentation phenotypes, histology, and treatments.CONCLUSION: Patients with MPM have increased risk of subsequent internal and cutaneous malignancies and may benefit from tight adherence to age-specific cancer screening.

  View details for PubMedID 30287320

• Inverse Relationship between Vitiligo-Related Genes and Skin Cancer Risk JOURNAL OF INVESTIGATIVE DERMATOLOGY Wu, W., Amos, C. I., Lee, J. E., Wei, Q., Sarin, K. Y., Han, J., 23andMe Res Team 2018; 138 (9): 2072–75

  View details for PubMedID 29580869

• Frequent basal cell cancer development is a clinical marker for inherited cancer susceptibility JCI INSIGHT Cho, H. G., Kuo, K. Y., Li, S., Bailey, I., Aasi, S., Chang, A. S., Oro, A. E., Tang, J. Y., Sarin, K. Y. 2018; 3 (15)

  Abstract

  Innate DNA repair mechanisms play a critical role in protecting skin keratinocytes from UV mutagenesis and skin cancer development. We hypothesized that individuals who develop frequent skin cancers may harbor germline defects in DNA repair genes and have increased predisposition to internal malignancies. We enrolled 61 patients with unusually frequent basal cell carcinoma (BCC) development, seen at Stanford Hospital and Clinics from January 2005 until December 2015, for germline analysis of 29 DNA repair genes. In parallel, a case-control retrospective review was performed to interrogate the association of malignancies with frequent BCC development in a large US medical insurance claims database (Truven), which included 13,264 individuals with 6 or more BCCs from 2007 to 2011. 19.7% of the frequent BCC cohort harbored pathogenic mutations in DNA repair genes: APC, BARD1, BRCA1, BRCA2, CDH1, CHEK2, MLH1, MSH2, MSH6, MUTYH, NBN, and PALB2. Individuals with 6 or more BCCs had an increased risk of other malignancies, with a 3.5-fold increase in the frequent BCC cohort and a 3.2-fold increase in the Truven database. Individuals who developed frequent BCCs have an increased prevalence of germline mutations in DNA repair genes and increased malignancy risk. Our data implicate frequent BCC development as an external marker of inherited cancer risk.

  View details for DOI 10.1172/jci.insight.122744

  View details for Web of Science ID 000441201300022

  View details for PubMedID 30089731

• Melanoma risk prediction using a multilocus genetic risk score in the Women's Health Initiative cohort JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Cho, H. G., Ransohoff, K. J., Yang, L., Hedlin, H., Assimes, T., Han, J., Stefanick, M., Tang, J. Y., Sarin, K. Y. 2018; 79 (1): 36-+

  View details for DOI 10.1016/j.jaad.2018.02.052

  View details for Web of Science ID 000438597000012

• TGF-beta, Fibronectin and Integrin alpha5beta1 Promote Invasion in Basal Cell Carcinoma. The Journal of investigative dermatology Kuonen, F., Surbeck, I., Sarin, K. Y., Dontenwill, M., Ruegg, C., Gilliet, M., Oro, A. E., Gaide, O. 2018

  Abstract

  Basal cell carcinoma (BCC) is the most frequent human cancer and is becoming an important health problem in an ageing population. Based on their clinical and histological characteristics, thick BCC are typically divided into low-risk nodular and high-risk infiltrative subtypes, although the underlying mechanisms are poorly understood. We have identified molecular mechanisms that explain the aggressiveness of high-risk infiltrative BCC, with a potential direct clinical impact. In this study, we first show that fibroblasts, TGFbeta and fibronectin are found preferentially in infiltrative human BCC. This allowed us to develop in vivo models for the study of infiltrative BCC, which in turn let us confirm the role of TGFbeta in inducing peritumoral fibronectin deposition and tumor infiltration. We then show that fibronectin promotes adhesion and migration of BCC cell lines through integrin alpha5beta1-mediated phosphorylation of focal adhesion kinase (FAK). Fittingly, inhibition of integrin alpha5beta1 and phospho-FAK both prevent fibronectin-induced migration of BCC cells in vitro as well as BCC infiltration in vivo. Altogether our results open important insights into the pathogenesis of aggressive infiltrative BCC, and identify integrin alpha5beta1 or FAK inhibition as promising strategies for the treatment of advanced BCC.

  View details for PubMedID 29758283

• Melanoma risk prediction using a multilocus genetic risk score in the Women's Health Initiative cohort. Journal of the American Academy of Dermatology Cho, H. G., Ransohoff, K. J., Yang, L., Hedlin, H., Assimes, T., Han, J., Stefanick, M., Tang, J. Y., Sarin, K. Y. 2018

  Abstract

  BACKGROUND: Single-nucleotide polymorphisms (SNPs) associated with melanoma have been identified though genome-wide association studies. However, the combined impact of these SNPs on melanoma development remains unclear, particularly in postmenopausal women who carry a lower melanoma risk.OBJECTIVE: We examine the contribution of a combined polygenic risk score on melanoma development in postmenopausal women.METHODS: Genetic risk scores were calculated using 21 genome-wide association study-significant SNPs. Their combined effect on melanoma development was evaluated in 19,102 postmenopausal white women in the clinical trial and observational study arms of the Women's Health Initiative dataset.RESULTS: Compared to the tertile of weighted genetic risk score with the lowest genetic risk, the women in the tertile with the highest genetic risk were 1.9 times more likely to develop melanoma (95% confidence interval 1.50-2.42). The incremental change in c-index from adding genetic risk scores to age were 0.075 (95% confidence interval 0.041-0.109) for incident melanoma.LIMITATIONS: Limitations include a lack of information on nevi count, Fitzpatrick skin type, family history of melanoma, and potential reporting and selection bias in the Women's Health Initiative cohort.CONCLUSION: Higher genetic risk is associated with increased melanoma prevalence and incidence in postmenopausal women, but current genetic information may have a limited role in risk prediction when phenotypic information is available.

  View details for PubMedID 29499294

• Azathioprine and risk of multiple keratinocyte cancers. Journal of the American Academy of Dermatology Cho, H. G., Kuo, K. Y., Xiao, K. n., Batra, P. n., Li, S. n., Tang, J. Y., Sarin, K. Y. 2018; 78 (1): 27–28.e1

  View details for PubMedID 28989107

• Azathioprine and risk of multiple keratinocyte cancers JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Cho, H. G., Kuo, K. Y., Xiao, K., Batra, P., Li, S., Tang, J. Y., Sarin, K. Y. 2018; 78 (1): 27-+

  View details for DOI 10.1016/j.jaad.2017.09.063

  View details for Web of Science ID 000417961700017

• Modulation of the Hedgehog signaling pathway in models of basal cell carcinoma by ATP-competitive PKCi inhibitors Roffey, J., Dillon, C., Oro, A. E., Mirza, A. N., Sarin, K. Y., Aasi, S. Z., Parker, P. J., Riou, P., Barton, C., Patel, B., Turnbull, A., Stanway, E., Fowler, K., Ott, G., Ator, M. AMER ASSOC CANCER RESEARCH. 2018

  View details for DOI 10.1158/1535-7163.TARG-17-LB-B32

  View details for Web of Science ID 000590008800478

• Pembrolizumab for advanced basal cell carcinoma: an investigator-initiated, proof-of-concept study. Journal of the American Academy of Dermatology Chang, A. L., Tran, D. C., Cannon, J. G., Li, S. n., Jeng, M. n., Patel, R. n., Van der Bokke, L. n., Pague, A. n., Brotherton, R. n., Rieger, K. E., Satpathy, A. T., Yost, K. E., Reddy, S. n., Sarin, K. n., Colevas, A. D. 2018

  View details for PubMedID 30145186

• Noncanonical hedgehog pathway activation through SRF-MKL1 promotes drug resistance in basal cell carcinomas. Nature medicine Whitson, R. J., Lee, A. n., Urman, N. M., Mirza, A. n., Yao, C. Y., Brown, A. S., Li, J. R., Shankar, G. n., Fry, M. A., Atwood, S. X., Lee, E. Y., Hollmig, S. T., Aasi, S. Z., Sarin, K. Y., Scott, M. P., Epstein, E. H., Tang, J. Y., Oro, A. E. 2018; 24 (3): 271–81

  Abstract

  Hedgehog pathway-dependent cancers can escape Smoothened (SMO) inhibition through mutations in genes encoding canonical hedgehog pathway components; however, around 50% of drug-resistant basal cell carcinomas (BCCs) lack additional variants of these genes. Here we use multidimensional genomics analysis of human and mouse drug-resistant BCCs to identify a noncanonical hedgehog activation pathway driven by the transcription factor serum response factor (SRF). Active SRF along with its coactivator megakaryoblastic leukemia 1 (MKL1) binds DNA near hedgehog target genes and forms a previously unknown protein complex with the hedgehog transcription factor glioma-associated oncogene family zinc finger-1 (GLI1), causing amplification of GLI1 transcriptional activity. We show that cytoskeletal activation through Rho and the formin family member Diaphanous (mDia) is required for SRF-MKL-driven GLI1 activation and for tumor cell viability. Remarkably, nuclear MKL1 staining served as a biomarker in tumors from mice and human subjects to predict tumor responsiveness to MKL inhibitors, highlighting the therapeutic potential of targeting this pathway. Thus, our study illuminates, for the first time, cytoskeletal-activation-driven transcription as a personalized therapeutic target for combatting drug-resistant malignancies.

  View details for PubMedID 29400712

  View details for PubMedCentralID PMC5839965

• Diagnostic Distinction of Malignant Melanoma and Benign Nevi by a Gene Expression Signature and Correlation to Clinical Outcomes CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Ko, J. S., Matharoo-Ball, B., Billings, S., Thomson, B. J., Tang, J. Y., Sarin, K. Y., Cai, E., Kim, J., Rock, C., Kimbrell, H. Z., Flake, D. D., Warf, M., Nelson, J., Davis, T., Miller, C., Rushton, K., Hartman, A., Wenstrup, R. J., Clarke, L. E. 2017; 26 (7): 1107–13

  Abstract

  Background: Histopathologic examination alone can be inadequate for diagnosis of certain melanocytic neoplasms. Recently, a 23-gene expression signature was clinically validated as an ancillary diagnostic test to differentiate benign nevi from melanoma. The current study assessed the performance of this test in an independent cohort of melanocytic lesions against clinically proven outcomes.Methods: Archival tissue from primary cutaneous melanomas and melanocytic nevi was obtained from four independent institutions and tested with the gene signature. Cases were selected according to pre-defined clinical outcome measures. Malignant lesions were defined as stage I-III primary cutaneous melanomas that produced distant metastases (metastatic to sites other than proximal sentinel lymph node(s)) following diagnosis of the primary lesion. Melanomas that were metastatic at the time of diagnosis, all re-excisions, and lesions with <10% tumor volume were excluded. Benign lesions were defined as cutaneous melanocytic lesions with no adverse long-term events reported.Results: Of 239 submitted samples, 182 met inclusion criteria and produced a valid gene expression result. This included 99 primary cutaneous melanomas with proven distant metastases and 83 melanocytic nevi. Median time to melanoma metastasis was 18 months. Median follow-up time for nevi was 74.9 months. The gene expression score differentiated melanoma from nevi with a sensitivity of 93.8% and a specificity of 96.2%.Conclusions: The results of gene expression testing closely correlate with long-term clinical outcomes of patients with melanocytic neoplasms.Impact: Collectively, this provides strong evidence that the gene signature adds valuable adjunctive information to aid in the accurate diagnosis of melanoma. Cancer Epidemiol Biomarkers Prev; 26(7); 1107-13. ©2017 AACR.

  View details for PubMedID 28377414

• Diagnostic distinction of malignant melanoma and benign nevi by a gene expression signature and correlation to clinical outcomes Kim, J., Ko, J., Matharoo-Ball, B., Billings, S., Thomson, B., Sarin, K., Rock, C., Flake, D., Clarke, L. MOSBY-ELSEVIER. 2017: AB100

  View details for Web of Science ID 000403369301013

• Genetic diseases associated with an increased risk of skin cancer development in childhood. Current opinion in pediatrics Fogel, A. L., Sarin, K. Y., Teng, J. M. 2017

  Abstract

  Childhood skin cancers are relatively rare and may indicate an underlying genetic disorder. The increasing elucidation of genetic pathways is changing the diagnosis and management of genetic skin cancer susceptibility syndromes. In this review, we provide an overview of genetic conditions that predispose to skin cancer development in childhood and signs that providers should assess when evaluating affected individuals.In basal cell nevus syndrome (BCNS), the patched2 (PTCH2) and suppressor of fused (SUFU) genes have been implicated in disease pathogenesis. The sonic hedgehog (SHH) pathway inhibitor vismodegib was shown in a placebo-controlled phase III randomized trial to reduce the tumor burden in patients with BCNS. Epidermolysis bullosa (EB) has been classified into four major types and more than 30 subtypes based partly on specific mutations, and best clinical practice guidelines for the management of cutaneous squamous cell carcinoma in EB have been developed. Oculocutaneous albinism (OCA) has been associated with new mutations in genes named OCA5, OCA6, and OCA7, bringing to the total number of culprit genes to seven (OCA1-OCA7).Advances in our understanding of genetic conditions that predispose to childhood skin cancer include new disease classification systems, management guidelines, and treatment options.

  View details for DOI 10.1097/MOP.0000000000000514

  View details for PubMedID 28525403

• Association study of genetic variation in DNA repair pathway genes and risk of basal cell carcinoma. International journal of cancer Lin, Y., Chahal, H. S., Wu, W., Cho, H. G., Ransohoff, K. J., Song, F., Tang, J. Y., Sarin, K. Y., Han, J. 2017

  Abstract

  DNA repair plays a critical role in protecting the genome from ultraviolet radiation and maintaining the genomic integrity of cells. Genetic variants in DNA repair-related genes can influence an individual's DNA repair capacity, which may be related to the risk of developing basal cell carcinoma (BCC). We comprehensively assessed the associations of 2,965 independent single-nucleotide polymorphisms (SNPs) across 165 DNA repair pathway genes with BCC risk in a genome-wide association meta-analysis totaling 17,187 BCC cases and 287,054 controls from two data sets. After multiple testing corrections, we identified three SNPs (rs2805831 upstream of XPA: OR = 0.93, P = 1.35 × 10(-6) ; rs659857 in exon of MUS81: OR = 1.06, P = 3.09 × 10(-6) and rs57343616 in 3' UTR of NABP2: OR = 1.11, P = 6.47 × 10(-6) ) as significantly associated with BCC risk in meta-analysis, and all of them were nominally significant in both data sets. Furthermore, rs659857 [T] was significantly associated with decreased expression of MUS81 mRNA in the expression quantitative trait locus (eQTL) analysis. Our findings suggest that the inherited common variation in three DNA repair genes-XPA, MUS81 and NABP2-may be involved in the development of BCC. To our knowledge, our study is the first report thoroughly examining the effects of SNPs across DNA repair pathway genes on BCC risk based on a genome-wide association meta-analysis.

  View details for DOI 10.1002/ijc.30786

  View details for PubMedID 28510302

• Correlates of multiple basal cell carcinoma in a retrospective cohort study: Sex, histologic subtypes, and anatomic distribution. Journal of the American Academy of Dermatology Kuo, K. Y., Batra, P., Cho, H. G., Li, S., Chahal, H. S., Rieger, K. E., Tang, J. Y., Sarin, K. Y. 2017

  View details for DOI 10.1016/j.jaad.2017.02.047

  View details for PubMedID 28392289

• Association between genetic variation within vitamin D receptor-DNA binding sites and risk of basal cell carcinoma. International journal of cancer Lin, Y., Chahal, H. S., Wu, W., Cho, H. G., Ransohoff, K. J., Dai, H., Tang, J. Y., Sarin, K. Y., Han, J. 2017

  Abstract

  An increasing number of studies have reported a protective association between vitamin D and cancer risk. The vitamin D endocrine system regulates transcriptional programs involved in inflammation, cell growth and differentiation through the binding of vitamin D receptor (VDR) to specific VDR elements. However, limited attention has been given to the role of variation within VDR binding sites in the development of basal cell carcinoma (BCC). Across 2,776 previously identified VDR binding sites, we identified 2,540 independent single-nucleotide polymorphisms (SNPs) and examined their associations with BCC risk in a genome-wide association meta-analysis totaling 17,187 BCC cases and 287,054 controls from two data sets. After multiple testing corrections, we identified two SNPs at new loci (rs16917546 at 10q21.1: odds ratio (OR) = 1.06, p = 3.16 × 10(-7) and rs79824801 at 12q13.3: OR = 1.10, p = 1.88 × 10(-5) ) for the first time as independently related to BCC risk in meta-analysis; and both SNPs were nominally significant in two data sets. In addition, the SNP rs3769823 within VDR binding site at a previously reported BCC susceptibility locus (2q33.1, rs13014235) also exhibited a significant association (OR = 1.12, p = 3.99 × 10(-18) ). A mutually adjusted model suggested that rs3769823 explained the signal in this region. Our findings support the hypothesis that inherited common variation in VDR binding sites affects the development of BCC.

  View details for DOI 10.1002/ijc.30634

  View details for PubMedID 28177523

• Incidence ratio of basal cell carcinoma to squamous cell carcinoma equalizes with age. Journal of the American Academy of Dermatology Chahal, H. S., Rieger, K. E., Sarin, K. Y. 2017; 76 (2): 353-354

  View details for DOI 10.1016/j.jaad.2016.08.019

  View details for PubMedID 28089000

• Diagnostic Distinction of Malignant Melanoma and Benign Nevi by a Gene Expression Signature and Correlation to Clinical Outcomes Ko, J., Matharoo-Ball, B., Billings, S., Thomson, B., Tang, J., Sarin, K., Cai, E., Kim, J., Rock, C., Kimbrell, H., Flake, D., Warf, M., Nelson, J., Davis, T., Miller, C., Rushton, K., Hartman, A., Wenstrup, R., Clarke, L. NATURE PUBLISHING GROUP. 2017: 132A

  View details for Web of Science ID 000394467300517

• Factors influencing and modifying the decision to pursue genetic testing for skin cancer risk. Journal of the American Academy of Dermatology Fogel, A. L., Jaju, P. D., Li, S., Halpern-Felsher, B., Tang, J. Y., Sarin, K. Y. 2017

  Abstract

  Across cancers, the decision to pursue genetic testing is influenced more by subjective than objective factors. However, skin cancer, which is more prevalent, visual, and multifactorial than many other malignancies, may offer different motivations for pursuing such testing.The primary objective was to determine factors influencing the decision to receive genetic testing for skin cancer risk. A secondary objective was to assess the impact of priming with health questions on the decision to receive testing.We distributed anonymous online surveys through ResearchMatch.org to assess participant health, demographics, motivations, and interest in pursuing genetic testing for skin cancer risk. Two surveys with identical questions but different question ordering were used to assess the secondary objective.We received 3783 responses (64% response rate), and 85.8% desired testing. Subjective factors, including curiosity, perceptions of skin cancer, and anxiety, were the most statistically significant determinants of the decision to pursue testing (P < .001), followed by history of sun exposure (odds ratio 1.85, P < .01) and history of skin cancer (odds ratio 0.5, P = .01). Age and family history of skin cancer did not influence this decision. Participants increasingly chose testing if first queried about health behaviors (P < .0001).The decision to pursue hypothetical testing may differ from in-clinic decision-making. Self-selected, online participants may differ from the general population. Surveys may be subject to response bias.The decision to pursue genetic testing for skin cancer is primarily determined by subjective factors, such as anxiety and curiosity. Health factors, including skin cancer history, also influenced decision-making. Priming with consideration of objective health factors can increase the desire to pursue testing.

  View details for DOI 10.1016/j.jaad.2016.11.050

  View details for PubMedID 28087134

• IFNγ-Dependent Tissue-Immune Homeostasis Is Co-opted in the Tumor Microenvironment. Cell Nirschl, C. J., Suárez-Fariñas, M. n., Izar, B. n., Prakadan, S. n., Dannenfelser, R. n., Tirosh, I. n., Liu, Y. n., Zhu, Q. n., Devi, K. S., Carroll, S. L., Chau, D. n., Rezaee, M. n., Kim, T. G., Huang, R. n., Fuentes-Duculan, J. n., Song-Zhao, G. X., Gulati, N. n., Lowes, M. A., King, S. L., Quintana, F. J., Lee, Y. S., Krueger, J. G., Sarin, K. Y., Yoon, C. H., Garraway, L. n., Regev, A. n., Shalek, A. K., Troyanskaya, O. n., Anandasabapathy, N. n. 2017; 170 (1): 127–41.e15

  Abstract

  Homeostatic programs balance immune protection and self-tolerance. Such mechanisms likely impact autoimmunity and tumor formation, respectively. How homeostasis is maintained and impacts tumor surveillance is unknown. Here, we find that different immune mononuclear phagocytes share a conserved steady-state program during differentiation and entry into healthy tissue. IFNγ is necessary and sufficient to induce this program, revealing a key instructive role. Remarkably, homeostatic and IFNγ-dependent programs enrich across primary human tumors, including melanoma, and stratify survival. Single-cell RNA sequencing (RNA-seq) reveals enrichment of homeostatic modules in monocytes and DCs from human metastatic melanoma. Suppressor-of-cytokine-2 (SOCS2) protein, a conserved program transcript, is expressed by mononuclear phagocytes infiltrating primary melanoma and is induced by IFNγ. SOCS2 limits adaptive anti-tumoral immunity and DC-based priming of T cells in vivo, indicating a critical regulatory role. These findings link immune homeostasis to key determinants of anti-tumoral immunity and escape, revealing co-opting of tissue-specific immune development in the tumor microenvironment.

  View details for PubMedID 28666115

• Combined inhibition of atypical PKC and histone deacetylase 1 is cooperative in basal cell carcinoma treatment. JCI insight Mirza, A. N., Fry, M. A., Urman, N. M., Atwood, S. X., Roffey, J. n., Ott, G. R., Chen, B. n., Lee, A. n., Brown, A. S., Aasi, S. Z., Hollmig, T. n., Ator, M. A., Dorsey, B. D., Ruggeri, B. R., Zificsak, C. A., Sirota, M. n., Tang, J. Y., Butte, A. n., Epstein, E. n., Sarin, K. Y., Oro, A. E. 2017; 2 (21)

  Abstract

  Advanced basal cell carcinomas (BCCs) circumvent Smoothened (SMO) inhibition by activating GLI transcription factors to sustain the high levels of Hedgehog (HH) signaling required for their survival. Unfortunately, there is a lack of efficacious therapies. We performed a gene expression-based drug repositioning screen in silico and identified the FDA-approved histone deacetylase (HDAC) inhibitor, vorinostat, as a top therapeutic candidate. We show that vorinostat only inhibits proliferation of BCC cells in vitro and BCC allografts in vivo at high dose, limiting its usefulness as a monotherapy. We leveraged this in silico approach to identify drug combinations that increase the therapeutic window of vorinostat and identified atypical PKC Ɩ/ʎ (aPKC) as a HDAC costimulator of HH signaling. We found that aPKC promotes GLI1-HDAC1 association in vitro, linking two positive feedback loops. Combination targeting of HDAC1 and aPKC robustly inhibited GLI1, lowering drug doses needed in vitro, in vivo, and ex vivo in patient-derived BCC explants. We identified a bioavailable and selective small-molecule aPKC inhibitor, bringing the pharmacological blockade of aPKC and HDAC1 into the realm of clinical possibility. Our findings provide a compelling rationale and candidate drugs for combined targeting of HDAC1 and aPKC in HH-dependent cancers.

  View details for PubMedID 29093271

• A survey of direct-to-consumer teledermatology services available to US patients: Explosive growth, opportunities and controversy. Journal of telemedicine and telecare Fogel, A. L., Sarin, K. Y. 2017; 23 (1): 19-25

  Abstract

  Introduction Direct-to-consumer (DTC) teledermatology is radically changing the way patients obtain dermatological care. Now, with a few clicks, patients can obtain dermatological consultations and prescription medications without a prior physician-patient relationship. To analyse all DTC teledermatology services available to US patients. Methods We performed Internet searches to identify DTC teledermatology services available through Internet webpages or through smartphone applications. For each service, the scope of care provided, cost, wait times, prescription policies and other relevant information were recorded. Results Twenty-two DTC teledermatology services are available to US patients in 45 states. Six (27%) services offer care from international physicians. Sixteen (73%) services allow patients to seek care for any reason, while six (27%) limit care to acne or anti-aging. The median reported response time for DTC teledermatology services is 48 hours from the time of patient request. The median consultation fee for companies providing care from US board-certified physicians is US$59. Across all services, consultation fees range from US$1.59 to US$250. Conclusions DTC teledermatology services are readily available to patients in most states. These services may reduce the cost of patient visits, expand access to care and increase patient convenience. However, the presence of services staffed by physicians who are not US board-certified, as well as the use of incautious language regarding prescription medications, is concerning.

  View details for DOI 10.1177/1357633X15624044

  View details for PubMedID 26729755

• Invasive Melanoma in a Patient with Congenital Ichthyosiform Erythroderma PEDIATRIC DERMATOLOGY Jaju, P., Novoa, R. A., Swetter, S. M., Sarin, K. Y. 2017; 34 (1): E35-E36

  Abstract

  We describe the case of a 26-year-old woman with a history of congenital ichthyosiform erythroderma (CIE) who initially presented with a stage IIA amelanotic melanoma on her forearm that was surgically excised. We also review the literature on CIE-associated skin cancers and discuss the possible contribution of ichthyosis to the risk of cutaneous malignancies. Our findings emphasize the importance of close lifelong skin cancer screening in individuals with CIE and highlight the unique malignancy risk of these individuals.

  View details for DOI 10.1111/pde.13012

  View details for Web of Science ID 000393955600008

• Basosquamous Carcinoma: Controversy, Advances, and Future Directions. Dermatologic surgery Tan, C. Z., Rieger, K. E., Sarin, K. Y. 2017; 43 (1): 23-31

  Abstract

  Basosquamous carcinoma is a rare cutaneous neoplasm that has caused considerable controversy as to its classification, pathogenesis, and management.To review and summarize current literature on the definition, pathogenesis, incidence, and management of basosquamous carcinoma.Through December 2015, an electronic search of the Pubmed database was performed using combinations of basosquamous carcinoma and metatypical basal cell carcinoma as search terms.A selection of 39 publications including case reports and series, retrospective studies, and systematic reviews of the literature were included. Descriptions of the definition of basosquamous carcinoma, clinical behavior, histopathological characteristics, current treatment therapies, and future advances are summarized.This systematic review provides a comprehensive overview of the current understanding of basosquamous carcinoma. Further study is required to elucidate the mechanisms driving the formation of this aggressive tumor.

  View details for DOI 10.1097/DSS.0000000000000815

  View details for PubMedID 27340741

• Tumor-Derived Suppressor of Fused Mutations Reveal Hedgehog Pathway Interactions PLOS ONE Urman, N. M., Mirza, A., Atwood, S. X., Whitson, R. J., Sarin, K. Y., Tang, J. Y., Oro, A. E. 2016; 11 (12)

  Abstract

  The Hedgehog pathway is a potent regulator of cellular growth and plays a central role in the development of many cancers including basal cell carcinoma (BCC). The majority of BCCs arise from mutations in the Patched receptor resulting in constitutive activation of the Hedgehog pathway. Secondary driver mutations promote BCC oncogenesis and occur frequently due to the high mutational burden resulting from sun exposure of the skin. Here, we uncover novel secondary mutations in Suppressor of Fused (SUFU), the major negative regulator of the Hedgehog pathway. SUFU normally binds to a Hedgehog transcriptional activator, GLI1, in order to prevent it from initiating transcription of Hedgehog target genes. We sequenced tumor-normal pairs from patients with early sporadic BCCs. This resulted in the discovery of nine mutations in SUFU, which were functionally investigated to determine whether they help drive BCC formation. Our results show that four of the SUFU mutations inappropriately activate the Hedgehog pathway, suggesting they may act as driver mutations for BCC development. Indeed, all four of the loss of function SUFU variants were found to disrupt its binding to GLI, leading to constitutive pathway activation. Our results from functional characterization of these mutations shed light on SUFU's role in Hedgehog signaling, tumor progression, and highlight a way in which BCCs can arise.

  View details for DOI 10.1371/journal.pone.0168031

  View details for Web of Science ID 000391222000030

  View details for PubMedID 28030567

  View details for PubMedCentralID PMC5193403

• Invasive Melanoma in a Patient with Congenital Ichthyosiform Erythroderma. Pediatric dermatology Jaju, P., Novoa, R. A., Swetter, S. M., Sarin, K. Y. 2016

  Abstract

  We describe the case of a 26-year-old woman with a history of congenital ichthyosiform erythroderma (CIE) who initially presented with a stage IIA amelanotic melanoma on her forearm that was surgically excised. We also review the literature on CIE-associated skin cancers and discuss the possible contribution of ichthyosis to the risk of cutaneous malignancies. Our findings emphasize the importance of close lifelong skin cancer screening in individuals with CIE and highlight the unique malignancy risk of these individuals.

  View details for DOI 10.1111/pde.13012

  View details for PubMedID 27813222

• Direct-to-consumer teledermatology services for pediatric patients: Room for improvement. Journal of the American Academy of Dermatology Fogel, A. L., Teng, J., Sarin, K. Y. 2016; 75 (5): 887-888

  Abstract

  Direct-to-consumer teledermatology is radically changing the way some patients obtain dermatologic care. Many direct-to-consumer teledermatology services offer care to patients younger than 18 years, but policies and standards are nonuniform. For pediatric patients, direct-to-consumer teledermatology is a substantial departure from in-person care. More consensus, standards, and guidelines are necessary.

  View details for DOI 10.1016/j.jaad.2016.08.002

  View details for PubMedID 27614530

• Assessment of Accuracy of Patient-Initiated Differential Diagnosis Generation by Google Reverse Image Searching. JAMA dermatology Ransohoff, J. D., Li, S., Sarin, K. Y. 2016; 152 (10): 1164-1166

  View details for DOI 10.1001/jamadermatol.2016.2096

  View details for PubMedID 27367170

• Effects of Combined Treatment With Arsenic Trioxide and Itraconazole in Patients With Refractory Metastatic Basal Cell Carcinoma. JAMA dermatology Ally, M. S., Ransohoff, K., Sarin, K., Atwood, S. X., Rezaee, M., Bailey-Healy, I., Kim, J., Beachy, P. A., Chang, A. L., Oro, A., Tang, J. Y., Colevas, A. D. 2016; 152 (4): 452-456

  Abstract

  Tumor resistance is an emerging problem for Smoothened (SMO) inhibitor-treated metastatic basal cell carcinoma (BCC). Arsenic trioxide and itraconazole antagonize the hedgehog (HH) pathway at sites distinct from those treated by SMO inhibitors.To determine whether administration of intravenous arsenic trioxide and oral itraconazole in patients with metastatic BCC is associated with a reduction in GLI1 messenger RNA expression in tumor and/or normal skin biopsy samples.Five men with metastatic BCC who experienced relapse after SMO inhibitor treatment underwent intravenous arsenic trioxide treatment for 5 days, every 28 days, and oral itraconazole treatment on days 6 to 28. Data were collected from April 10 to November 14, 2013. Follow-up was completed on October 3, 2015, and data were analyzed from June 5 to October 6, 2015.The primary outcome was the change in messenger RNA levels of the GLI family zinc finger 1 (GLI1) gene (HH-pathway target gene) in biopsy specimens of normal skin or BCC before and after treatment. Secondary objectives were evaluation of tumor response and tolerability.Of the 5 patients (mean [SD] age, 52 [9] years; age range, 43-62 years), 3 completed 3 cycles of treatment and 2 discontinued treatment early owing to disease progression or adverse events. Adverse effects included grade 2 transaminitis and grade 4 leukopenia with a grade 3 infection. Overall, arsenic trioxide and itraconazole reduced GLI1 messenger RNA levels by 75% from baseline (P < .001). The best overall response after 3 treatment cycles was stable disease in 3 patients.Targeting the HH pathway with sequential arsenic trioxide and itraconazole treatment is a feasible treatment for metastatic BCC. Although some patients experienced stable disease for 3 months, none had tumor shrinkage, which may be owing to transient GLI1 suppression with sequential dosing. Continuous dosing may be required to fully inhibit the HH pathway and achieve clinical response.

  View details for DOI 10.1001/jamadermatol.2015.5473

  View details for PubMedID 26765315

• An Investigator-Initiated Open-Label Trial of Sonidegib in Advanced Basal Cell Carcinoma Patients Resistant to Vismodegib CLINICAL CANCER RESEARCH Danial, C., Sarin, K. Y., Oro, A. E., Chang, A. L. 2016; 22 (6): 1325-1329

  Abstract

  To assess the tumor response to the smoothened (SMO) inhibitor, sonidegib (LDE225), in patients with an advanced basal cell carcinoma (BCC) resistant to treatment with vismodegib (GDC0449).Nine patients with an advanced BCC that was previously resistant to treatment with vismodegib were given sonidegib in this investigational, open-label study. Tumor response was determined using the response evaluation criteria in solid tumors. SMO mutations were identified using biopsy samples from the target BCC location.The median duration of treatment with sonidegib was 6 weeks (range, 3-58 weeks). Five patients experienced progressive disease with sonidegib. Three patients experienced stable disease and discontinued sonidegib either due to adverse events (n = 1) or due to election for surgery (n = 2). The response of one patient was not evaluable. SMO mutations with in vitro data suggesting resistance to Hh pathway inhibition were identified in 5 patients, and none of these patients experienced responses while on sonidegib.Patients with advanced BCCs that were previously resistant to treatment with vismodegib similarly demonstrated treatment resistance with sonidegib. Patients who have developed treatment resistance to an SMO inhibitor may continue to experience tumor progression in response to other SMO inhibitors. Clin Cancer Res; 22(6); 1325-9. ©2015 AACR.

  View details for DOI 10.1158/1078-0432.CCR-15-1588

  View details for Web of Science ID 000373358900006

  View details for PubMedID 26546616

  View details for PubMedCentralID PMC4794361

• Familial skin cancer syndromes Increased risk of nonmelanotic skin cancers and extracutaneous tumors JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Jaju, P. D., Ransohoff, K. J., Tang, J. Y., Sarin, K. Y. 2016; 74 (3): 437-451

  Abstract

  Nonmelanoma skin cancers (NMSCs) represent the most common malignancies worldwide, with reported incidence rising each year. Both cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), as well as other NMSCs, represent complex diseases with a combination of environmental and genetic risk factors. In general, hereditary cancer syndromes that increase the risk of NMSC fall under several broad categories: those associated with immunodeficiencies, those that affect skin pigmentation, and those that perturb key molecular pathways involved in the pathogenesis of NMSCs. Many of the syndromes are also associated with extracutaneous manifestations, including internal malignancies; therefore, most require a multidisciplinary management approach with a medical geneticist. Finally, dermatologists play a critical role in the diagnosis and management of these conditions, because cutaneous findings are often the presenting manifestations of disease.

  View details for DOI 10.1016/j.jaad.2015.08.073

  View details for Web of Science ID 000370372300008

  View details for PubMedID 26892653

• Familial skin cancer syndromes Increased melanoma risk JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Ransohoff, K. J., Jaju, P. D., Tang, J. Y., Carbone, M., Leachman, S., Sarin, K. Y. 2016; 74 (3): 423-434

  Abstract

  Phenotypic traits, such as red hair and freckling, increase melanoma risk by 2- to 3-fold. In addition, approximately 10% of melanomas are caused by inherited germline mutations that increase melanoma risk from 4- to >1000-fold. This review highlights the key genes responsible for inherited melanoma, with an emphasis on when a patient should undergo genetic testing. Many genetic syndromes associated with increased melanoma risk are also associated with an increased risk of other cancers. Identification of these high-risk patients is essential for preventive behavior reinforcement, genetic counseling, and ensuring other required cancer screenings.

  View details for DOI 10.1016/j.jaad.2015.09.070

  View details for PubMedID 26892652

• A survey of direct-to-consumer teledermatology services available to US patients: Explosive growth, opportunities, and controversy Journal of telemedicine and telecare Fogel, A. L., Sarin, K. Y. 2016
• Effects of combined treatment with arsenic trioxide and itraconazole in patients with refractory metastatic basal cell carcinoma JAMA Dermatology Sarin, K. Y., Ally, M. S., Ransohoff, K. J., Atwood, S. X., Rezaee, M. 2016: 1–5

  Abstract

  Tumor resistance is an emerging problem for Smoothened (SMO) inhibitor-treated metastatic basal cell carcinoma (BCC). Arsenic trioxide and itraconazole antagonize the hedgehog (HH) pathway at sites distinct from those treated by SMO inhibitors.To determine whether administration of intravenous arsenic trioxide and oral itraconazole in patients with metastatic BCC is associated with a reduction in GLI1 messenger RNA expression in tumor and/or normal skin biopsy samples.Five men with metastatic BCC who experienced relapse after SMO inhibitor treatment underwent intravenous arsenic trioxide treatment for 5 days, every 28 days, and oral itraconazole treatment on days 6 to 28. Data were collected from April 10 to November 14, 2013. Follow-up was completed on October 3, 2015, and data were analyzed from June 5 to October 6, 2015.The primary outcome was the change in messenger RNA levels of the GLI family zinc finger 1 (GLI1) gene (HH-pathway target gene) in biopsy specimens of normal skin or BCC before and after treatment. Secondary objectives were evaluation of tumor response and tolerability.Of the 5 patients (mean [SD] age, 52 [9] years; age range, 43-62 years), 3 completed 3 cycles of treatment and 2 discontinued treatment early owing to disease progression or adverse events. Adverse effects included grade 2 transaminitis and grade 4 leukopenia with a grade 3 infection. Overall, arsenic trioxide and itraconazole reduced GLI1 messenger RNA levels by 75% from baseline (P < .001). The best overall response after 3 treatment cycles was stable disease in 3 patients.Targeting the HH pathway with sequential arsenic trioxide and itraconazole treatment is a feasible treatment for metastatic BCC. Although some patients experienced stable disease for 3 months, none had tumor shrinkage, which may be owing to transient GLI1 suppression with sequential dosing. Continuous dosing may be required to fully inhibit the HH pathway and achieve clinical response.

  View details for DOI 10.1001/jamadermatol.2015.5473

• Familial skin cancer syndromes: Increased melanoma risk Journal of The American Academy of Dermatology Jaju, P. D., Ransohoff, K. J., Tang, J. Y., Sarin, K. Y. 2016; 74 (3): 423-434
• Familial skin cancer syndromes: Increased risk of nonmelanotic skin cancers and extracutaneous tumors Journal of The American Academy of Dermatology Sarin, K. Y., Tang, J. Y., Ransohoff, K. J., Jaju, P. D. 2016; 74 (3): 437-451
• The digital age of melanoma management: detection and diagnostics. Melanoma management Fogel, A. L., Sarin, K. 2015; 2 (4): 383-391

  Abstract

  New technologies are increasingly impacting the way melanoma is detected and diagnosed. Devices, software and diagnostics abound, ranging from smartphone applications that purport to predict which lesions are likely to be malignant, to genomic analysis of low-stage melanomas to predict metastatic risk. The purpose of this review is to concisely update practitioners on the research behind the latest tools available for melanoma detection and diagnosis, as well as the implications of these technologies for melanoma management.

  View details for DOI 10.2217/mmt.15.31

  View details for PubMedID 30190865

  View details for PubMedCentralID PMC6094706

• Activity of Type I and Type II Interferons in Dermatomyositis Skin Is Correlated with Characteristic Pathologic Features Leatham, H. W., Rieger, K., Chung, L., Li, S., Higgs, B. W., Yao, Y., Sarin, K., Fiorentino, D. WILEY-BLACKWELL. 2015

  View details for Web of Science ID 000370860202208

• Squamous Change in Basal-Cell Carcinoma with Drug Resistance. New England journal of medicine Ransohoff, K. J., Tang, J. Y., Sarin, K. Y. 2015; 373 (11): 1079-1082

  View details for DOI 10.1056/NEJMc1504261

  View details for PubMedID 26352826

• Smoothened Inhibitors in Sonic Hedgehog Subgroup Medulloblastoma. Journal of clinical oncology Ransohoff, K. J., Sarin, K. Y., Tang, J. Y. 2015; 33 (24): 2692-2694

  View details for DOI 10.1200/JCO.2015.62.2225

  View details for PubMedID 26195713

• Rolling the Genetic Dice: Neutral and Deleterious Smoothened Mutations in Drug-Resistant Basal Cell Carcinoma. journal of investigative dermatology Atwood, S. X., Sarin, K. Y., Li, J. R., Yao, C. Y., Urman, N. M., Chang, A. L., Tang, J. Y., Oro, A. E. 2015; 135 (8): 2138-2141

  View details for DOI 10.1038/jid.2015.115

  View details for PubMedID 25801792

• A subdermal source: contact dermatitis. American journal of medicine Fogel, A. L., Longmire, M., Rieger, K. E., Sarin, K. Y. 2015; 128 (6): 578-581

  View details for DOI 10.1016/j.amjmed.2015.02.005

  View details for PubMedID 25747191

• Personal genomics in dermatology: Characteristics of patients who undergo genetic testing for melanoma risk Fogel, A., Sarin, K. MOSBY-ELSEVIER. 2015: AB99

  View details for Web of Science ID 000360942901129

• Genomic analysis of smoothened inhibitor resistance in Basal cell carcinoma. Cancer cell Sharpe, H. J., Pau, G., Dijkgraaf, G. J., Basset-Seguin, N., Modrusan, Z., Januario, T., Tsui, V., Durham, A. B., Dlugosz, A. A., Haverty, P. M., Bourgon, R., Tang, J. Y., Sarin, K. Y., Dirix, L., Fisher, D. C., Rudin, C. M., Sofen, H., Migden, M. R., Yauch, R. L., de Sauvage, F. J. 2015; 27 (3): 327-341

  Abstract

  Smoothened (SMO) inhibitors are under clinical investigation for the treatment of several cancers. Vismodegib is approved for the treatment of locally advanced and metastatic basal cell carcinoma (BCC). Most BCC patients experience significant clinical benefit on vismodegib, but some develop resistance. Genomic analysis of tumor biopsies revealed that vismodegib resistance is associated with Hedgehog (Hh) pathway reactivation, predominantly through mutation of the drug target SMO and to a lesser extent through concurrent copy number changes in SUFU and GLI2. SMO mutations either directly impaired drug binding or activated SMO to varying levels. Furthermore, we found evidence for intra-tumor heterogeneity, suggesting that a combination of therapies targeting components at multiple levels of the Hh pathway is required to overcome resistance.

  View details for DOI 10.1016/j.ccell.2015.02.001

  View details for PubMedID 25759019

• An investigator-initiated open label trial of sonidegib in advanced basal cell carcinoma patients resistant to vismodegib Clinical cancer research: an official journal of the American Association for Cancer Research Sarin, K. Y., Oro, A. E., Chang, A. L., Danial, C. 2015

  View details for DOI 10.1158/1078-0432.CCR-15-1588

• The digital age of melanoma management: detection and diagnostics Future Medicine Fogel, A. L., Sarin, K. Y. 2015; 2 (4): 383-391

  Abstract

  New technologies are increasingly impacting the way melanoma is detected and diagnosed. Devices, software and diagnostics abound, ranging from smartphone applications that purport to predict which lesions are likely to be malignant, to genomic analysis of low-stage melanomas to predict metastatic risk. The purpose of this review is to concisely update practitioners on the research behind the latest tools available for melanoma detection and diagnosis, as well as the implications of these technologies for melanoma management.

  View details for DOI 10.2217/mmt.15.31

  View details for PubMedCentralID PMC6094706

• Dermatologic applications of direct-to-consumer genomic analysis. Journal of the American Academy of Dermatology Fogel, A. L., Azizi, N., Tang, J., Sarin, K. Y. 2014; 71 (5): 993-995

  View details for DOI 10.1016/j.jaad.2014.04.066

  View details for PubMedID 25437956

• Activating HRAS Mutation in Nevus Spilus. journal of investigative dermatology Sarin, K. Y., McNiff, J. M., Kwok, S., Kim, J., Khavari, P. A. 2014; 134 (6): 1766-1768

  View details for DOI 10.1038/jid.2014.6

  View details for PubMedID 24390138

• Dermatologic applications of direct-to-consumer genomic analysis Fogel, A., Tang, J., Sarin, K., Azizi, N. MOSBY-ELSEVIER. 2014: AB80

  View details for Web of Science ID 000360583900317

• Dermatomyositis associated with capecitabine in the setting of malignancy JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Chen, F. W., Zhou, X., Egbert, B. M., Swetter, S. M., Sarin, K. Y. 2014; 70 (2): E47-E48

  View details for DOI 10.1016/j.jaad.2013.10.025

  View details for Web of Science ID 000329851500013

  View details for PubMedID 24438983

• Dermatomyositis associated with capecitabine in the setting of malignancy. Journal of the American Academy of Dermatology Chen, F. W., Zhou, X., Egbert, B. M., Swetter, S. M., Sarin, K. Y. 2014; 70 (2): e47-8

  View details for DOI 10.1016/j.jaad.2013.10.025

  View details for PubMedID 24438983

• Activating HRAS mutation in agminated Spitz nevi arising in a nevus spilus. JAMA dermatology Sarin, K. Y., Sun, B. K., Bangs, C. D., Cherry, A., Swetter, S. M., Kim, J., Khavari, P. A. 2013; 149 (9): 1077-1081

  Abstract

  IMPORTANCE Spitz nevi are benign melanocytic proliferations that can sometimes be clinically and histopathologically difficult to distinguish from melanoma. Agminated Spitz nevi have been reported to arise spontaneously, in association with an underlying nevus spilus, or after radiation or chemotherapy. However, to our knowledge, the genetic mechanism for this eruption has not been described. OBSERVATIONS We report a case of agminated Spitz nevi arising in a nevus spilus and use exome sequencing to identify a clonal activating point mutation in HRAS (GenBank 3265) (c.37G→C) in the Spitz nevi and underlying nevus spilus. We also identify a secondary copy number increase involving HRAS on chromosome 11p, which occurs during the development of the Spitz nevi. CONCLUSIONS AND RELEVANCE Our results reveal an activating HRAS mutation in a nevus spilus that predisposes to the formation of Spitz nevi. In addition, we demonstrate a copy number increase in HRAS as a "second hit" during the formation of agminated Spitz nevi, which suggests that both multiple Spitz nevi and solitary Spitz nevi may arise through similar molecular pathways. In addition, we describe a unique investigative approach for the discovery of genetic alterations in Spitz nevi.

  View details for DOI 10.1001/jamadermatol.2013.4745

  View details for PubMedID 23884457

• Mosaic Activating RAS Mutations in Nevus Sebaceus and Nevus Sebaceus Syndrome JOURNAL OF INVESTIGATIVE DERMATOLOGY Sun, B. K., Saggini, A., Sarin, K. Y., Kim, J., Benjamin, L., LeBoit, P. E., Khavari, P. A. 2013; 133 (3): 824-827

  View details for DOI 10.1038/jid.2012.377

  View details for PubMedID 23096709

• Molecular Profiling to Diagnose a Case of Atypical Dermatomyocitis Journal of Investigative Dermatology Sarin, K., Chung, L., Kim, J., Higgs, B., Jallal, B., Yao, Y., Fiorentino, D. 2013; 133 (12): 2796-2799
• Treatment of Recalcitrant Eosinophilic Cellulitis With Adalimumab ARCHIVES OF DERMATOLOGY Sarin, K. Y., Fiorentino, D. 2012; 148 (9): 990-992

  View details for Web of Science ID 000308883500002

  View details for PubMedID 22986848

• Reversible cell-cycle entry in adult kidney podocytes through regulated control of telomerase and Wnt signaling. Nature medicine Shkreli, M., Sarin, K. Y., Pech, M. F., Papeta, N., Chang, W., Brockman, S. A., Cheung, P., Lee, E., Kuhnert, F., Olson, J. L., Kuo, C. J., Gharavi, A. G., D'Agati, V. D., Artandi, S. E. 2012; 18 (1): 111-119

  Abstract

  Mechanisms of epithelial cell renewal remain poorly understood in the mammalian kidney, particularly in the glomerulus, a site of cellular damage in chronic kidney disease. Within the glomerulus, podocytes--differentiated epithelial cells crucial for filtration--are thought to lack substantial capacity for regeneration. Here we show that podocytes rapidly lose differentiation markers and enter the cell cycle in adult mice in which the telomerase protein component TERT is conditionally expressed. Transgenic TERT expression in mice induces marked upregulation of Wnt signaling and disrupts glomerular structure, resulting in a collapsing glomerulopathy resembling those in human disease, including HIV-associated nephropathy (HIVAN). Human and mouse HIVAN kidneys show increased expression of TERT and activation of Wnt signaling, indicating that these are general features of collapsing glomerulopathies. Silencing transgenic TERT expression or inhibiting Wnt signaling through systemic expression of the Wnt inhibitor Dkk1 in either TERT transgenic mice or in a mouse model of HIVAN results in marked normalization of podocytes, including rapid cell-cycle exit, re-expression of differentiation markers and improved filtration barrier function. These data reveal an unexpected capacity of podocytes to reversibly enter the cell cycle, suggest that podocyte renewal may contribute to glomerular homeostasis and implicate the telomerase and Wnt-β-catenin pathways in podocyte proliferation and disease.

  View details for DOI 10.1038/nm.2550

  View details for PubMedID 22138751

• Reversible cell-cycle entry in adult kidney podocytes through regulated control of telomerase and Wnt signaling NATURE MEDICINE Shkreli, M., Sarin, K. Y., Pech, M. F., Papeta, N., Chang, W., Brockman, S. A., Cheung, P., Lee, E., Kuhnert, F., Olson, J. L., Kuo, C. J., Gharavi, A. G., D'Agati, V. D., Artandi, S. E. 2012; 18 (1): 111-119

  View details for DOI 10.1038/nm.2550

  View details for Web of Science ID 000299018600036

• TERT promotes epithelial proliferation through transcriptional control of a Myc- and Wnt-related developmental program PLOS GENETICS Choi, J., Southworth, L. K., Sarin, K. Y., Venteicher, A. S., Ma, W., Chang, W., Cheung, P., Jun, S., Artandi, M. K., Shah, N., Kim, S. K., Artandi, S. E. 2008; 4 (1)

  Abstract

  Telomerase serves a critical role in stem cell function and tissue homeostasis. This role depends on its ability to synthesize telomere repeats in a manner dependent on the reverse transcriptase (RT) function of its protein component telomerase RT (TERT), as well as on a novel pathway whose mechanism is poorly understood. Here, we use a TERT mutant lacking RT function (TERT(ci)) to study the mechanism of TERT action in mammalian skin, an ideal tissue for studying progenitor cell biology. We show that TERT(ci) retains the full activities of wild-type TERT in enhancing keratinocyte proliferation in skin and in activating resting hair follicle stem cells, which triggers initiation of a new hair follicle growth phase and promotes hair synthesis. To understand the nature of this RT-independent function for TERT, we studied the genome-wide transcriptional response to acute changes in TERT levels in mouse skin. We find that TERT facilitates activation of progenitor cells in the skin and hair follicle by triggering a rapid change in gene expression that significantly overlaps the program controlling natural hair follicle cycling in wild-type mice. Statistical comparisons to other microarray gene sets using pattern-matching algorithms revealed that the TERT transcriptional response strongly resembles those mediated by Myc and Wnt, two proteins intimately associated with stem cell function and cancer. These data show that TERT controls tissue progenitor cells via transcriptional regulation of a developmental program converging on the Myc and Wnt pathways.

  View details for DOI 10.1371/journal.pgen.0040010

  View details for Web of Science ID 000255378700011

  View details for PubMedID 18208333

  View details for PubMedCentralID PMC2211538

• Aging, graying and loss of melanocyte stem cells STEM CELL REVIEWS Sarin, K. Y., Artandi, S. E. 2007; 3 (3): 212-217

  Abstract

  Hair graying is one of the prototypical signs of human aging. Maintenance of hair pigmentation is dependent on the presence and functionality of melanocytes, neural crest derived cells which synthesize pigment for growing hair. The melanocytes, themselves, are maintained by a small number of stem cells which reside in the bulge region of the hair follicle. The recent characterization of the melanocyte lineage during aging has significantly accelerated our understanding of how age-related changes in the melanocyte stem cell compartment contribute to hair graying. This review will discuss our current understanding of hair graying, drawing on evidence from human and mouse studies, and consider the contribution of melanocyte stem cells to this process. Furthermore, using the melanocyte lineage as an example, it will discuss common theories of tissue and stem cell aging.

  View details for DOI 10.1007/s12015-007-0028-0

  View details for Web of Science ID 000249929800004

  View details for PubMedID 17917134

• Conditional telomerase induction causes proliferation of hair follicle stem cells NATURE Sarin, K. Y., Cheung, P., Gilison, D., Lee, E., Tennen, R. I., Wang, E., Artandi, M. K., Oro, A. E., Artandi, S. E. 2005; 436 (7053): 1048-1052

  Abstract

  TERT, the protein component of telomerase, serves to maintain telomere function through the de novo addition of telomere repeats to chromosome ends, and is reactivated in 90% of human cancers. In normal tissues, TERT is expressed in stem cells and in progenitor cells, but its role in these compartments is not fully understood. Here we show that conditional transgenic induction of TERT in mouse skin epithelium causes a rapid transition from telogen (the resting phase of the hair follicle cycle) to anagen (the active phase), thereby facilitating robust hair growth. TERT overexpression promotes this developmental transition by causing proliferation of quiescent, multipotent stem cells in the hair follicle bulge region. This new function for TERT does not require the telomerase RNA component, which encodes the template for telomere addition, and therefore operates through a mechanism independent of its activity in synthesizing telomere repeats. These data indicate that, in addition to its established role in extending telomeres, TERT can promote proliferation of resting stem cells through a non-canonical pathway.

  View details for DOI 10.1038/nature03836

  View details for Web of Science ID 000231263900057

  View details for PubMedID 16107853

  View details for PubMedCentralID PMC1361120