Kavita Sarin, M.D./ Ph.D., is an Assistant Professor of Dermatology. She has an academic interest in Personalized Medicine, focused on the integration of genetic and clinical patient data to inform disease susceptibility, stratify prognosis, and direct treatments in dermatologic disease. She sees patients in medical dermatology at Portola Valley and directs a specialized Skin Cancer Genetics clinic.
- Basal Cell Carcinoma
- Precision Dermatology
- Skin Cancers
- Genetic Skin Disease
Assistant Professor in Dermatology, Stanford University Medical Center (2013 - Present)
Clinical Instructor in Dermatology, Stanford University Medical Center (2012 - 2013)
Honors & Awards
Medical Dermatology Career Development Award, Dermatology Foundation (2014-2017)
F32 NRSA Ruth L. Kirschstein National Research Service Award, National Institutes of Health (2013-2014)
Translational Research and Medicine Award, Stanford University (2013-2014)
Scholar Travel Award, American Association of Cancer Research (2006)
Medical Scientist Training Program Scholarship, National Institutes of Health (2000-2008)
President's Scholar, Stanford University (1996-2000)
Unsung Hero Award, NBC (1996)
Boards, Advisory Committees, Professional Organizations
Member, Children's Health Research Institute (2017 - Present)
Fellow, American Academy of Dermatology (2009 - Present)
Member, Society of Investigative Dermatology (2014 - Present)
Member, Dermatology Foundation (2014 - Present)
Internship:Santa Clara Valley Medical Center Radiology Residency (2009) CA
Board Certification: Dermatology, American Board of Dermatology (2012)
Residency:Stanford University - Dept of Dermatology (2012) CA
Medical Education:Stanford University Medical Center (2008) CA
PhD, Stanford University- Dept of Genetics, CA (2006)
BS, Stanford University- Computer Science, CA (2000)
Current Research and Scholarly Interests
My research encompasses two main areas: 1) Using next-generation RNA, whole genome, and exome sequencing, we are investigating the genetic alterations involved in skin cancer progression, response to therapy, and other clinical outcomes and 2) We are developing and implementing genome-wide genetic risk prediction assessments for skin cancer into clinical use and studying the impact of this information on patient care.
Analysis of Cutaneous and Hematologic Disorders by High-Throughput Nucleic Acid Sequencing
The goal of this study is to identify genetic changes associated with the initiation, progression, and treatment response of response of cutaneous and hematologic disorders using recently developed high-throughput sequencing technologies. The improved understanding of the genetic changes associated with cutaneous and hematologic disorders may lead to improved diagnostic, prognostic and therapeutic options for these disorders.
Stanford is currently not accepting patients for this trial. For more information, please contact Alexander Ungewickell, 650-723-6661.
Topical Remetinostat in Treating Patient With Cutaneous Basal Cell Cancer
This phase II trial studies how well remetinostat works in treating patients with skin basal cell cancer. Remetinostat may slow the growth of basal cell cancer cells.
Stanford is currently not accepting patients for this trial. For more information, please contact Irene Bailey-Healy, 408-892-7261.
Genetic alterations in vismodegib resistant basal cell carcinomas, Stanford University (July 2014 - June 2017)
The goal of this project is to identify genetic alterations that confer resistance to Smoothened inhibitor therapy in basal cell carcinoma.
Development and implementation of a Genetic Risk Score for skin cancer prediction, Stanford University (9/1/2013 - 12/2014)
The study aims to develop, implement and assess the impact of a genetic risk score to predict skin cancer risk based on genotypic data with the goal of understanding the barriers and benefits of implementing genetic risk analysis into clinical care
TGF-beta, Fibronectin and Integrin alpha5beta1 Promote Invasion in Basal Cell Carcinoma.
The Journal of investigative dermatology
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 DOI 10.1016/j.jid.2018.04.029
View details for PubMedID 29758283
- Identification of Atorvastatin for Moderate to Severe Hidradenitis through Drug Repositioning Using Public Gene Expression Datasets JOURNAL OF INVESTIGATIVE DERMATOLOGY 2018; 138 (5): 1209–12
Melanoma risk prediction using a multilocus genetic risk score in the Women's Health Initiative cohort.
Journal of the American Academy of Dermatology
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 DOI 10.1016/j.jaad.2018.02.052
View details for PubMedID 29499294
- Detecting Chemotherapeutic Skin Adverse Reactions in Social Health Networks Using Deep Learning. JAMA oncology 2018; 4 (4): 581–83
Noncanonical hedgehog pathway activation through SRF-MKL1 promotes drug resistance in basal cell carcinomas.
2018; 24 (3): 271–81
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 DOI 10.1038/nm.4476
View details for PubMedID 29400712
View details for PubMedCentralID PMC5839965
- Azathioprine and risk of multiple keratinocyte cancers. Journal of the American Academy of Dermatology 2018; 78 (1): 27–28.e1
Diagnostic Distinction of Malignant Melanoma and Benign Nevi by a Gene Expression Signature and Correlation to Clinical Outcomes
CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION
2017; 26 (7): 1107–13
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 DOI 10.1158/1055-9965.EPI-16-0958
View details for Web of Science ID 000415229200016
View details for PubMedID 28377414
Genetic diseases associated with an increased risk of skin cancer development in childhood.
Current opinion in pediatrics
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
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 2017
- Postzygotic Mutations in Beta-Actin are Associated with Becker's Nevus and Becker's Nevus Syndrome. journal of investigative dermatology 2017
Two-stage genome-wide association study identifies a novel susceptibility locus associated with melanoma.
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
Association between genetic variation within vitamin D receptor-DNA binding sites and risk of basal cell carcinoma.
International journal of cancer
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 2017; 76 (2): 353-354
Factors influencing and modifying the decision to pursue genetic testing for skin cancer risk.
Journal of the American Academy of Dermatology
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.
2017; 170 (1): 127–41.e15
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 DOI 10.1016/j.cell.2017.06.016
View details for PubMedID 28666115
Genomic Stability in Syndromic Basal Cell Carcinoma.
The Journal of investigative dermatology
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 DOI 10.1016/j.jid.2017.09.048
View details for PubMedID 29111235
A survey of direct-to-consumer teledermatology services available to US patients: Explosive growth, opportunities and controversy.
Journal of telemedicine and telecare
2017; 23 (1): 19-25
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 2017; 34 (1): E35-E36
Basosquamous Carcinoma: Controversy, Advances, and Future Directions.
2017; 43 (1): 23-31
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
2016; 11 (12)
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.
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
2016; 75 (5): 887-888
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 2016; 152 (10): 1164-1166
- Identification of Alpha-Adrenergic Agonists as Potential Therapeutic Agents for Dermatomyositis through Drug-Repurposing Using Public Expression Datasets. journal of investigative dermatology 2016; 136 (7): 1517-1520
Effects of Combined Treatment With Arsenic Trioxide and Itraconazole in Patients With Refractory Metastatic Basal Cell Carcinoma.
2016; 152 (4): 452-456
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  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
2016; 22 (6): 1325-1329
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
2016; 74 (3): 437-451
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
2016; 74 (3): 423-434
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 Web of Science ID 000370372300007
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 2016
Genome-wide association study identifies novel susceptibility loci for cutaneous squamous cell carcinoma.
2016; 7: 12048-?
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
Genome-wide association study identifies 14 novel risk alleles associated with basal cell carcinoma.
2016; 7: 12510-?
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
Effects of combined treatment with arsenic trioxide and itraconazole in patients with refractory metastatic basal cell carcinoma
View details for DOI 10.1001/jamadermatol.2015.5473
- Familial skin cancer syndromes: Increased melanoma risk Journal of The American Academy of Dermatology 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 2016; 74 (3): 437-451
- Mutations in the Kinetochore Gene KNSTRN in Basal Cell Carcinoma. journal of investigative dermatology 2015; 135 (12): 3197-3200
- Squamous Change in Basal-Cell Carcinoma with Drug Resistance NEW ENGLAND JOURNAL OF MEDICINE 2015; 373 (11): 1079-1082
- Smoothened Inhibitors in Sonic Hedgehog Subgroup Medulloblastoma. Journal of clinical oncology 2015; 33 (24): 2692-2694
- Rolling the Genetic Dice: Neutral and Deleterious Smoothened Mutations in Drug-Resistant Basal Cell Carcinoma. journal of investigative dermatology 2015; 135 (8): 2138-2141
- A subdermal source: contact dermatitis. American journal of medicine 2015; 128 (6): 578-581
Genomic analysis of smoothened inhibitor resistance in Basal cell carcinoma.
2015; 27 (3): 327-341
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
Smoothened variants explain the majority of drug resistance in Basal cell carcinoma.
2015; 27 (3): 342-353
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
View details for PubMedCentralID PMC4357167
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
View details for DOI 10.1158/1078-0432.CCR-15-1588
The digital age of melanoma management: detection and diagnostics
2015; 2 (4): 383-391
View details for DOI 10.2217/mmt.15.31
- Dermatologic applications of direct-to-consumer genomic analysis. Journal of the American Academy of Dermatology 2014; 71 (5): 993-995
- Activating HRAS Mutation in Nevus Spilus. journal of investigative dermatology 2014; 134 (6): 1766-1768
- Dermatomyositis associated with capecitabine in the setting of malignancy JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY 2014; 70 (2): E47-E48
Activating HRAS mutation in agminated Spitz nevi arising in a nevus spilus.
2013; 149 (9): 1077-1081
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 2013; 133 (3): 824-827
- Molecular Profiling to Diagnose a Case of Atypical Dermatomyocitis Journal of Investigative Dermatology 2013; 133 (12): 2796-2799
- Treatment of Recalcitrant Eosinophilic Cellulitis With Adalimumab ARCHIVES OF DERMATOLOGY 2012; 148 (9): 990-992
Reversible cell-cycle entry in adult kidney podocytes through regulated control of telomerase and Wnt signaling.
2012; 18 (1): 111-119
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 2012; 18 (1): 111-119
TERT promotes epithelial proliferation through transcriptional control of a Myc- and Wnt-related developmental program
2008; 4 (1)
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
2007; 3 (3): 212-217
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
2005; 436 (7053): 1048-1052
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