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    University - Scholar Department: School of Medicine Position: Medical Fellow

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  • Mail Code: 5151

All Publications

  • CD22 CAR T cells demonstrate high response rates and safety in pediatric and adult B-ALL: Phase 1b results. Leukemia Schultz, L. M., Jeyakumar, N., Kramer, A. M., Sahaf, B., Srinagesh, H., Shiraz, P., Agarwal, N., Hamilton, M., Erickson, C., Jacobs, A., Moon, J., Baggott, C., Arai, S., Bharadwaj, S., Johnston, L. J., Liedtke, M., Lowsky, R., Meyer, E., Negrin, R., Rezvani, A., Shizuru, J., Sidana, S., Egeler, E., Mavroukakis, S., Tunuguntla, R., Gkitsas-Long, N., Retherford, A., Brown, A. K., Gramstrap-Petersen, A. L., Ibañez, R. M., Feldman, S. A., Miklos, D. B., Mackall, C. L., Davis, K. L., Frank, M., Ramakrishna, S., Muffly, L. 2024

    Abstract

    Chimeric antigen receptor (CAR) T cells targeting CD22 (CD22-CAR) provide a therapeutic option for patients with CD22+ malignancies with progression after CD19-directed therapies. Using on-site, automated, closed-loop manufacturing, we conducted parallel Phase 1b clinical trials investigating a humanized CD22-CAR with 41BB costimulatory domain in children and adults with heavily treated, relapsed/refractory (r/r) B-ALL. Of 19 patients enrolled, 18 had successful CD22-CAR manufacturing, and 16 patients were infused. High grade (3-4) cytokine release syndrome (CRS) and immune effector-cell-associated neurotoxicity syndrome (ICANS) each occurred in only one patient; however, three patients experienced immune-effector-cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS). Twelve of 16 patients (75%) achieved CR with an overall 56% MRD-negative CR rate. Duration of response was overall limited (median 77 days), and CD22 expression was downregulated in 4/12 (33%) available samples at relapse. In summary, we demonstrate that closed-loop manufacturing of CD22-CAR T cells is feasible and is associated with a favorable safety profile and high CR rates in pediatric and adult r/r B-ALL, a cohort with limited CD22-CAR reporting.

    View details for DOI 10.1038/s41375-024-02220-y

    View details for PubMedID 38491306

    View details for PubMedCentralID 4993814

  • CAR19 Therapy Drives Expansion of Clonal Hematopoiesis and Associated Cytopenias Hamilton, M. P., Sworder, B. J., Alig, S. K., Good, Z., Boegeholz, J., Schroers-Martin, J., Tamaresis, J., Esfahani, M., Lu, Y., Olsen, M., Liu, C., Ehlinger, Z., Desai, M., Liu-Fei, F., Muffly, L. S., Negrin, R. S., Arai, S., Johnston, L., Lowsky, R., Meyer, E. H., Rezvani, A. R., Shizuru, J., Weng, W., Shiraz, P., Sidana, S., Bharadwaj, S., Smith, M., Dahiya, S., Sahaf, B., Diehn, M., Frank, M. J., Mackall, C. L., Kurtz, D. M., Miklos, D. B., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2023

    View details for DOI 10.1182/blood-2023-182522

    View details for Web of Science ID 001159306701117

  • Distinct Circulating Genomic Features of Classical Hodgkin Lymphoma of Older Adults Rossi, C., Boegeholz, J., Alig, S. K., Garofalo, A., Esfahani, M., Schroers-Martin, J., Olsen, M., Kang, X., Kurtz, D. M., Sugio, T., Hamilton, M. P., Andre, M., Casasnovas, R., Fornecker, L., Diehn, M., Ghesquieres, H., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2023

    View details for DOI 10.1182/blood-2023-178257

    View details for Web of Science ID 001159740307115

  • Inferred Gene Expression By Cell-Free DNA Profiling Allows Noninvasive Lymphoma Classification Mutter, J. A., Esfahani, M., Schroers-Martin, J., Alig, S. K., Hamilton, M. P., Sworder, B. J., Tessoulin, B., Boegeholz, J., Flerlage, T., Flerlage, J. E., Binkley, M. S., Sugio, T., Rossi, C., Olsen, M., Liu, C., Le Gouill, S., Kurtz, D. M., Diehn, M., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2023

    View details for DOI 10.1182/blood-2023-186853

    View details for Web of Science ID 001159306701002

  • An Integrated Multimodal Framework for Noninvasive TCL Disease Detection and Monitoring Sugio, T., Shukla, N., Khodadoust, M. S., Nesselbush, M., Kato, K., Alig, S. K., Boegeholz, J., Schroers-Martin, J., Esfahani, M., Mutter, J. A., Garofalo, A., Jun, S., Hamilton, M. P., Rossi, C., Olsen, M., Liu, C., Akashi, K., Diehn, M., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2023

    View details for DOI 10.1182/blood-2023-180492

    View details for Web of Science ID 001159306706091

  • Manufacturing of a Subsequent Autologous CAR-T Product after Prior CAR-T Is Safe and Feasible Su, Y., Kramer, A., Hamilton, M. P., Agarwal, N., Feldman, S., Sahaf, B., Kuo, A., Mackall, C. L., Muffly, L. S., Miklos, D. B., Frank, M. J. AMER SOC HEMATOLOGY. 2023

    View details for DOI 10.1182/blood-2023-185413

    View details for Web of Science ID 001159306704061

  • Transcriptional Profiling Associated with CD22 CAR T Cell Clinical Response in LBCL Kramer, A., Hamilton, M. P., Prabhu, S., Desai, M., Kuo, A., Ehlinger, Z., Agarwal, N., Su, Y., Gkitsas, N., Fowler, C., Keerthi, V., Retherford, A., Klysz, D., Tunuguntla, R., Feldman, S., Sahaf, B., Baird, J. H., Muffly, L. S., Mackall, C. L., Miklos, D. B., Good, Z., Frank, M. J. AMER SOC HEMATOLOGY. 2023

    View details for DOI 10.1182/blood-2023-187615

    View details for Web of Science ID 001159306708064

  • Impact of Obesity on Efficacy, Safety, and Expansion Kinetics of Chimeric Antigen Receptor-T (CAR T) Therapy in Patients with Relapsed or Refractory Large B Cell Lymphoma (LBCL) Goyal, A., Bharadwaj, S., Lee, D., Lau, E., Hamilton, M. P., Jensen, A., Sahaf, B., Syal, S., Patil, S., Cancilla, J. E., Latchford, T., Weng, W., Smith, M., Frank, M. J., Miklos, D. B., Dahiya, S. AMER SOC HEMATOLOGY. 2023

    View details for DOI 10.1182/blood-2023-186828

    View details for Web of Science ID 001159740305129

  • Long-Term Efficacy and Immune Reconstitution with Bendamustine As a Lymphodepleting Agent for Axicabtagene Ciloleucel (Axi-Cel) in Patients with Refractory or Relapsed Large B-Cell Lymphoma (LBCL) Bharadwaj, S., Lau, E., Goyal, A., Hamilton, M. P., Srinagesh, H., Jensen, A., Syal, S., Mallampet, J., Latchford, T., Sahaf, B., Weng, W., Smith, M., Maecker, H. T., Frank, M. J., Miklos, D. B., Dahiya, S. AMER SOC HEMATOLOGY. 2023

    View details for DOI 10.1182/blood-2023-188166

    View details for Web of Science ID 001159900800079

  • Post-CAR-T Minimal Residual Disease (MRD) Monitoring in Mantle Cell Lymphoma Enables Early Relapse Detection Ananth, S., Su, Y., Hamilton, M. P., Agarwal, N., Weng, W., Dahiya, S., Bharadwaj, S., Mallampet, J., Smith, M., Kong, K., Twoy, A., Miklos, D. B., Frank, M. J. AMER SOC HEMATOLOGY. 2023

    View details for DOI 10.1182/blood-2023-188338

    View details for Web of Science ID 001159306706144

  • Analysis of PET-CT Derived Radiomic Biomarkers with Efficacy, Safety, and Expansion of Axicabtagene Ciloleucel (Axi-Cel) in Patients with Relapsed or Refractory Large B-Cell Lymphoma (LBCL) Bharadwaj, S., Lau, E., Hashmi, A., Hamilton, M. P., Jensen, A., Goyal, A., Marar, M., Lee, C., Ananth, S., Sahaf, B., Mallampet, J., Ehlinger, Z., Syal, S., Patil, S., Guo, H., Smith, M., Weng, W., Frank, M. J., Binkley, M. S., Miklos, D. B., Dahiya, S. AMER SOC HEMATOLOGY. 2023

    View details for DOI 10.1182/blood-2023-187617

    View details for Web of Science ID 001159306708098

  • Zika virus co-opts miRNA networks to persist in placental niches detected by spatial transcriptomics. American journal of obstetrics and gynecology Barrozo, E. R., Seferovic, M. D., Hamilton, M. P., Moorshead, D. N., Jochum, M. D., Do, T., O'Neil, D. S., Suter, M. A., Aagaard, K. M. 2023

    Abstract

    Zika virus (ZIKV) congenital infection evades double-stranded RNA detection and may persist in the placenta for the duration of pregnancy, without accompanying overt histopathologic inflammation. Understanding how viruses can persist and replicate in the placenta, without causing overt cellular or tissue damage, is fundamental to deciphering mechanisms of maternal-fetal vertical transmission.Placenta-specific microRNAs (miRNAs) are believed to be a tenet of viral resistance at the maternal-fetal interface. We aimed to test the hypothesis that ZIKV functionally disrupts placental miRNAs, enabling viral persistence and fetal pathogenesis.To test this hypothesis, we utilized orthogonal approaches in human and murine experimental models. In primary human trophoblast cultures (n=5 donor placentae), we performed high-throughput sequencing crosslinking and immunoprecipitation (AGO-HITS-CLIP) to identify any significant alterations in the functional loading of miRNAs and their targets onto the RNA-induced silencing complex (RISC). Trophoblasts from same-donors were split, and infected with a contemporary first-passage ZIKV strain HN16 (MOI=1 plaque forming unit per cell) or mock infected. To functionally cross-validate miRNA-mRNA interactions, we compared our AGO-HITS-CLIP results with an independent analysis of published (Lum et al., 2019) bulk RNA-seq data from human placental disc specimens (n=3 subjects; ZIKV-positive in 1st, 2nd, or 3rd-trimester, CD45- cells sorted by flow-cytometry) compared to uninfected controls (n=2 subjects). To investigate the importance of these miRNA and RNAi networks in ZIKV pathogenesis, we utilized a gnotobiotic mouse model uniquely susceptible to ZIKV infection. We evaluate if small-molecule enhancement of miRNA and RNAi pathways with enoxacin influenced ZIKV pathogenesis (n=20 dams total yielding 187 fetal specimens). Lastly, placentae (n=14 total) from this mouse model were analyzed with Visium spatial transcriptomics (9,743 spatial transcriptomes) to identify potential ZIKV-associated alterations in immune microenvironments.We found that ZIKV infection of primary human trophoblast cells led to an unexpected disruption of placental miRNA regulation networks. Compared to uninfected controls, ZIKV-infected placentae had significantly altered SLC12A8, SDK1, and VLDLR RISC-loading and transcript levels (-22; adjusted p-value<0.05, Wald-test with FDR correction q<0.05). In silico miRNA target analyses revealed 26 of 119 transcripts (22%) in the TGF-β Signaling Pathway were targeted by miRNAs which were found to be dysregulated following ZIKV infection in trophoblasts. In gnotobiotic mice, relative to mock controls, ZIKV-associated fetal pathogenesis included fetal growth restriction (p=0.036) and viral persistence in placental tissue (p=0.011). Moreover, spatial transcriptomics of murine placentae revealed that ZIKV-specific placental niches were defined by significant upregulation of complement cascade components and coordinated changes in TGF-β gene expression. Finally, treatment of ZIKV-infected mice with enoxacin abolished placental ZIKV persistence, rescued the associated fetal growth restriction, and ZIKV-associated transcriptional changes in placental immune microenvironments were no longer observed.These results collectively suggest that (i) ZIKV infection and persistence is associated with functionally perturbed miRNA and RNAi pathways specifically related to immune regulation in placental microenvironments, and (ii) enhancement of placental miRNA and RNAi pathways in mice rescued ZIKV-associated pathogenesis, specifically persistence of viral transcripts in placental microenvironments and fetal growth restriction.

    View details for DOI 10.1016/j.ajog.2023.08.012

    View details for PubMedID 37598997

  • Chimeric Antigen Receptor T-Cell Therapy in Aggressive B-Cell Lymphoma. Hematology/oncology clinics of North America Hamilton, M. P., Miklos, D. B. 2023

    Abstract

    Chimeric antigen receptor (CAR) T-cell therapy is a revolutionary therapy increasingly used in the treatment of non-Hodgkin B-cell lymphoma. This review focuses on the use of CAR T-cell therapy in aggressive B-cell lymphoma including clinical indications, known short- and long-term toxicity, mechanisms of CAR T-cell efficacy and tumor resistance, and future directions in the treatment of aggressive lymphoma with CAR T-cell therapy.

    View details for DOI 10.1016/j.hoc.2023.05.007

    View details for PubMedID 37349153

  • Determinants of resistance to engineered T cell therapies targeting CD19 in large B cell lymphomas. Cancer cell Sworder, B. J., Kurtz, D. M., Alig, S. K., Frank, M. J., Shukla, N., Garofalo, A., Macaulay, C. W., Shahrokh Esfahani, M., Olsen, M. N., Hamilton, J., Hosoya, H., Hamilton, M., Spiegel, J. Y., Baird, J. H., Sugio, T., Carleton, M., Craig, A. F., Younes, S. F., Sahaf, B., Sheybani, N. D., Schroers-Martin, J. G., Liu, C. L., Oak, J. S., Jin, M. C., Beygi, S., Hüttmann, A., Hanoun, C., Dührsen, U., Westin, J. R., Khodadoust, M. S., Natkunam, Y., Majzner, R. G., Mackall, C. L., Diehn, M., Miklos, D. B., Alizadeh, A. A. 2022

    Abstract

    Most relapsed/refractory large B cell lymphoma (r/rLBCL) patients receiving anti-CD19 chimeric antigen receptor (CAR19) T cells relapse. To characterize determinants of resistance, we profiled over 700 longitudinal specimens from two independent cohorts (n = 65 and n = 73) of r/rLBCL patients treated with axicabtagene ciloleucel. A method for simultaneous profiling of circulating tumor DNA (ctDNA), cell-free CAR19 (cfCAR19) retroviral fragments, and cell-free T cell receptor rearrangements (cfTCR) enabled integration of tumor and both engineered and non-engineered T cell effector-mediated factors for assessing treatment failure and predicting outcomes. Alterations in multiple classes of genes are associated with resistance, including B cell identity (PAX5 and IRF8), immune checkpoints (CD274), and those affecting the microenvironment (TMEM30A). Somatic tumor alterations affect CAR19 therapy at multiple levels, including CAR19 T cell expansion, persistence, and tumor microenvironment. Further, CAR19 T cells play a reciprocal role in shaping tumor genotype and phenotype. We envision these findings will facilitate improved chimeric antigen receptor (CAR) T cells and personalized therapeutic approaches.

    View details for DOI 10.1016/j.ccell.2022.12.005

    View details for PubMedID 36584673

  • Determinants of Resistance to Engineered T-Cell Therapies Targeting CD19 in Large B-Cell Lymphomas Sworder, B., Kurtz, D. M., Alig, S. K., Frank, M. J., Shukla, N. D., Garofalo, A., Macaulay, C., Esfahani, M., Olsen, M., Hamilton, J., Hosoya, H., Hamilton, M. P., Spiegel, J. Y., Baird, J. H., Carleton, M., Craig, A. M., Younes, S. F., Sahaf, B., Sheybani, N., Schroers-Martin, J., Liu, C., Oak, J. S., Jin, M. C., Beygi, S., Huttmann, A., Hanoun, C., Duhrsen, U., Westin, J., Khodadoust, M. S., Natkunam, Y., Majzner, R. G., Mackall, C. L., Diehn, M., Miklos, D. B., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2022: 1301-1303

    View details for DOI 10.1182/blood-2022-165545

    View details for Web of Science ID 000893223201129

  • Higher Rates of Severe Infection and Persistent Cytopenias in Long-Term CAR19 Responders Than after Autologous HCT: A Single Institution Study of 139 Subjects Hamilton, M. P., Liu-Fei, F. C., Alig, S. K., Tamaresis, J., Esfahani, M., Good, Z., Sworder, B., Schroers-Martin, J., Liu, C., Severinsen, F., Hanson, P. J., Lu, Y., Lowsky, R., Negrin, R. S., Meyer, E. H., Smith, M., Bharadwaj, S., Shizuru, J. A., Sidana, S., Shiraz, P., Rezvani, A. R., Johnston, L. J., Weng, W., Arai, S., Muffly, L., Dahiya, S., Diehn, M., Kurtz, D. M., Sahaf, B., Mackall, C. L., Frank, M. J., Miklos, D. B., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2022: 7545-7547

    View details for DOI 10.1182/blood-2022-165600

    View details for Web of Science ID 000893230300247

  • The Development of Carhlh after Axicabtagene Ciloleucel Is Associated with Poor Outcomes Philip, S., Srinagesh, H. K., Hamilton, M. P., Gentille, C., Mina, A., Arai, S., Johnston, L. J., Lowsky, R., Meyer, E. H., Negrin, R. S., Rezvani, A. R., Shiraz, P., Shizuru, J. A., Sidana, S., Weng, W., Bharadwaj, S., Dahiya, S., Muffly, L., Smith, M., Miklos, D. B., Frank, M. J. AMER SOC HEMATOLOGY. 2022: 12775-12777

    View details for DOI 10.1182/blood-2022-170877

    View details for Web of Science ID 000893230305401

  • Analysis of Bendamustine Lymphodepletion, CD19 CART Expansion, Safety and Efficacy in Patients with Rel/Ref NonHodgkin Lymphoma Bharadwaj, S., Hamilton, M. P., Sahaf, B., Tamaresis, J., Patil, S., Hanson, P. J., Latchford, T., Arai, S., Johnston, L. J., Lowsky, R., Negrin, R. S., Rezvani, A. R., Shizuru, J. A., Meyer, E. H., Shiraz, P., Sidana, S., Smith, M., Weng, W., Muffly, L., Mackall, C. L., Frank, M. J., Miklos, D. B., Dahiya, S. AMER SOC HEMATOLOGY. 2022: 10371-10373

    View details for DOI 10.1182/blood-2022-170759

    View details for Web of Science ID 000893230303169

  • Post-infusion CAR T-Reg cells identify patients resistant to CD19-CAR therapy NATURE MEDICINE Good, Z., Spiegel, J. Y., Sahaf, B., Malipatlolla, M. B., Ehlinger, Z. J., Kurra, S., Desai, M. H., Reynolds, W. D., Lin, A., Vandris, P., Wu, F., Prabhu, S., Hamilton, M. P., Tamaresis, J. S., Hanson, P. J., Patel, S., Feldman, S. A., Frank, M. J., Baird, J. H., Muffly, L., Claire, G. K., Craig, J., Kong, K. A., Wagh, D., Coller, J., Bendall, S. C., Tibshirani, R. J., Plevritis, S. K., Miklos, D. B., Mackall, C. L. 2022

    Abstract

    Approximately 60% of patients with large B cell lymphoma treated with chimeric antigen receptor (CAR) T cell therapies targeting CD19 experience disease progression, and neurotoxicity remains a challenge. Biomarkers associated with resistance and toxicity are limited. In this study, single-cell proteomic profiling of circulating CAR T cells in 32 patients treated with CD19-CAR identified that CD4+Helios+ CAR T cells on day 7 after infusion are associated with progressive disease and less severe neurotoxicity. Deep profiling demonstrated that this population is non-clonal and manifests hallmark features of T regulatory (TReg) cells. Validation cohort analysis upheld the link between higher CAR TReg cells with clinical progression and less severe neurotoxicity. A model combining expansion of this subset with lactate dehydrogenase levels, as a surrogate for tumor burden, was superior for predicting durable clinical response compared to models relying on each feature alone. These data credential CAR TReg cell expansion as a novel biomarker of response and toxicity after CAR T cell therapy and raise the prospect that this subset may regulate CAR T cell responses in humans.

    View details for DOI 10.1038/s41591-022-01960-7

    View details for Web of Science ID 000852940800007

    View details for PubMedID 36097223

  • Reverse fate mapping of CD19-targeted CAR T cells in patients with large B-cell lymphoma Good, Z., Hamilton, M. P., Spiegel, J. Y., Kurra, S., Desai, M., Prabhu, S., Yang, E., Ozawa, M. G., Hanson, P. J., Wu, F., Frank, M. J., Baird, J. H., Muffly, L., Claire, G. K., Craig, J., Kong, K. A., Wagh, D., Coller, J., Plevritis, S. K., Sahaf, B., Miklos, D. B., Mackall, C. L. AMER ASSOC CANCER RESEARCH. 2022

    View details for Web of Science ID 000892509507391

  • Pan-cancer analysis of whole genomes NATURE Campbell, P. J., Getz, G., Korbel, J. O., Stuart, J. M., Jennings, J. L., Stein, L. D., Perry, M. D., Nahal-Bose, H. K., Ouellette, B., Li, C. H., Rheinbay, E., Nielsen, G., Sgroi, D. C., Wu, C., Faquin, W. C., Deshpande, V., Boutros, P. C., Lazar, A. J., Hoadley, K. A., Louis, D. N., Dursi, L., Yung, C. K., Bailey, M. H., Saksena, G., Raine, K. M., Buchhalter, I., Kleinheinz, K., Schlesner, M., Zhang, J., Wang, W., Wheeler, D. A., Ding, L., Simpson, J. T., O'Connor, B. D., Yakneen, S., Ellrott, K., Miyoshi, N., Butler, A. P., Royo, R., Shorser, S., Vazquez, M., Rausch, T., Tiao, G., Waszak, S. M., Rodriguez-Martin, B., Shringarpure, S., Wu, D., Demidov, G. M., Delaneau, O., Hayashi, S., Imoto, S., Habermann, N., Segre, A., Garrison, E., Cafferkey, A., Alvarez, E. G., Maria Heredia-Genestar, J., Muyas, F., Drechsel, O., Bruzos, A. L., Temes, J., Zamora, J., Baez-Ortega, A., Kim, H., Mashl, R., Ye, K., DiBiase, A., Huang, K., Letunic, I., McLellan, M. D., Newhouse, S. J., Shmaya, T., Kumar, S., Wedge, D. C., Wright, M. H., Yellapantula, V. D., Gerstein, M., Khurana, E., Marques-Bonet, T., Navarro, A., Bustamante, C. D., Siebert, R., Nakagawa, H., Easton, D. F., Ossowski, S., Tubio, J. C., De La Vega, F. M., Estivill, X., Yuen, D., Mihaiescu, G. L., Omberg, L., Ferretti, V., Sabarinathan, R., Pich, O., Gonzalez-Perez, A., Weiner, A., Fittall, M. W., Demeulemeester, J., Tarabichi, M., Roberts, N. D., Van Loo, P., Cortes-Ciriano, I., Urban, L., Park, P., Bin Zhu, Pitkaenen, E., Li, Y., Saini, N., Klimczak, L. J., Weischenfeldt, J., Sidiropoulos, N., Alexandrov, L. B., Rabionet, R., Escaramis, G., Bosio, M., Holik, A. Z., Susak, H., Prasad, A., Erkek, S., Calabrese, C., Raeder, B., Harrington, E., Mayes, S., Turner, D., Juul, S., Roberts, S. A., Song, L., Koster, R., Mirabello, L., Hua, X., Tanskanen, T. J., Tojo, M., Chen, J., Aaltonen, L. A., Ratsch, G., Schwarz, R. F., Butte, A. J., Brazma, A., Chanock, S. J., Chatterjee, N., Stegle, O., Harismendy, O., Bova, G., Gordenin, D. A., Haan, D., Sieverling, L., Feuerbach, L., Chalmers, D., Joly, Y., Knoppers, B., Molnar-Gabor, F., Phillips, M., Thorogood, A., Townend, D., Goldman, M., Fonseca, N. A., Xiang, Q., Craft, B., Pineiro-Yanez, E., Munoz, A., Petryszak, R., Fullgrabe, A., Al-Shahrour, F., Keays, M., Haussler, D., Weinstein, J., Huber, W., Valencia, A., Papatheodorou, I., Zhu, J., Fan, Y., Torrents, D., Bieg, M., Chen, K., Chong, Z., Cibulskis, K., Eils, R., Fulton, R. S., Gelpi, J. L., Gonzalez, S., Gut, I. G., Hach, F., Heinold, M., Hu, T., Huang, V., Hutter, B., Jaeger, N., Jung, J., Kumar, Y., Lalansingh, C., Leshchiner, I., Livitz, D., Ma, E. Z., Maruvka, Y. E., Milovanovic, A., Nielsen, M., Paramasivam, N., Pedersen, J., Puiggros, M., Sahinalp, S., Sarrafi, I., Stewart, C., Stobbe, M. D., Wala, J. A., Wang, J., Wendl, M., Werner, J., Wu, Z., Xue, H., Yamaguchi, T. N., Yellapantula, V., Davis-Dusenbery, B. N., Grossman, R. L., Kim, Y., Heinold, M. C., Hinton, J., Jones, D. R., Menzies, A., Stebbings, L., Hess, J. M., Rosenberg, M., Dunford, A. J., Gupta, M., Imielinski, M., Meyerson, M., Beroukhim, R., Reimand, J., Dhingra, P., Favero, F., Dentro, S., Wintersinger, J., Rudneva, V., Park, J., Hong, E., Heo, S., Kahles, A., Kjong-Van Lehmann, Soulette, C. M., Shiraishi, Y., Liu, F., He, Y., Demircioglu, D., Davidson, N. R., Greger, L., Li, S., Liu, D., Stark, S. G., Zhang, F., Amin, S. B., Bailey, P., Chateigner, A., Frenkel-Morgenstern, M., Hou, Y., Huska, M. R., Kilpinen, H., Lamaze, F. C., Li, C., Li, X., Li, X., Liu, X., Marin, M. G., Markowski, J., Nandi, T., Ojesina, A., Pan-Hammarstrom, Q., Park, P. J., Pedamallu, C., Su, H., Tan, P., Teh, B., Wang, J., Xiong, H., Ye, C., Yung, C., Zhang, X., Zheng, L., Zhu, S., Awadalla, P., Creighton, C. J., Wu, K., Yang, H., Goke, J., Zhang, Z., Brooks, A. N., Martincorena, I., Rubio-Perez, C., Juul, M., Schumacher, S., Shapira, O., Tamborero, D., Mularoni, L., Hornshoj, H., Deu-Pons, J., Muinos, F., Bertl, J., Guo, Q., Bazant, W., Barrera, E., Al-Sedairy, S. T., Aretz, A., Bell, C., Betancourt, M., Buchholz, C., Calvo, F., Chomienne, C., Dunn, M., Edmonds, S., Green, E., Gupta, S., Hutter, C. M., Jegalian, K., Jones, N., Lu, Y., Nakagama, H., Nettekoven, G., Planko, L., Scott, D., Shibata, T., Shimizu, K., Stratton, M. R., Yugawa, T., Tortora, G., VijayRaghavan, K., Zenklusen, J. C., Knoppers, B. M., Aminou, B., Bartolome, J., Boroevich, K. A., Boyce, R., Buchanan, A., Byrne, N. J., Chen, Z., Cho, S., Choi, W., Clapham, P., Dow, M. T., Dursi, L., Eils, J., Farcas, C., Fayzullaev, N., Flicek, P., Heath, A. P., Hofmann, O., Hong, J. H., Hudson, T. J., Huebschmann, D., Ivkovic, S., Jeon, S., Jiao, W., Kabbe, R., Kerssemakers, J. 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    Abstract

    Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1-3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10-18.

    View details for DOI 10.1038/s41586-020-1969-6

    View details for Web of Science ID 000529097800007

    View details for PubMedID 32025007

    View details for PubMedCentralID PMC7025898

  • Cancer LncRNA Census reveals evidence for deep functional conservation of long noncoding RNAs in tumorigenesis COMMUNICATIONS BIOLOGY Carlevaro-Fita, J., Lanzos, A., Feuerbach, L., Hong, C., Mas-Ponte, D., Pedersen, J., Johnson, R., Abascal, F., Amin, S. B., Bader, G. D., Barenboim, J., Beroukhim, R., Bertl, J., Boroevich, K. A., Brunak, S., Campbell, P. J., Carlevaro-Fita, J., Chakravarty, D., Chan, C., Chen, K., Choi, J., Deu-Pons, J., Dhingra, P., Diamanti, K., Feuerbach, L., Fink, J., Fonseca, N. A., Frigola, J., Gambacorti-Passerini, C., Garsed, D. W., Gerstein, M., Getz, G., Gonzalez-Perez, A., Guo, Q., Gut, I. G., Haan, D., Hamilton, M. P., Haradhvala, N. J., Harmanci, A. O., Helmy, M., Herrmann, C., Hess, J. M., Hobolth, A., Hodzic, E., Hong, C., Hornshoj, H., Isaev, K., Izarzugaza, J. G., Johnson, T. A., Juul, M., Juul, R., Kahles, A., Kahraman, A., Kellis, M., Khurana, E., Kim, J., Kim, J. K., Kim, Y., Komorowski, J., Korbel, J. O., Kumar, S., Lanzos, A., Larsson, E., Lawrence, M. S., Lee, D., Lehmann, K., Li, S., Li, X., Lin, Z., Liu, E., Lochovsky, L., Lou, S., Madsen, T., Marchal, K., Martincorena, I., Martinez-Fundichely, A., Maruvka, Y. E., McGillivray, P. D., Meyerson, W., Muinos, F., Mularoni, L., Nakagawa, H., Nielsen, M., Paczkowska, M., Park, K., Park, K., Pedersen, J., Pich, O., Pons, T., Pulido-Tamayo, S., Raphael, B. J., Reimand, J., Reyes-Salazar, I., Reyna, M. A., Rheinbay, E., Rubin, M. A., Rubio-Perez, C., Sabarinathan, R., Sahinalp, S., Saksena, G., Salichos, L., Sander, C., Schumacher, S. E., Shackleton, M., Shapira, O., Shen, C., Shrestha, R., Shuai, S., Sidiropoulos, N., Sieverling, L., Sinnott-Armstrong, N., Stein, L. D., Stuart, J. M., Tamborero, D., Tiao, G., Tsunoda, T., Umer, H. M., Uuskula-Reimand, L., Valencia, A., Vazquez, M., Verbeke, L. C., Wadelius, C., Wadi, L., Wang, J., Warrell, J., Waszak, S. M., Weischenfeldt, J., Wheeler, D. A., Wu, G., Yu, J., Zhang, J., Zhang, X., Zhang, Y., Zhao, Z., Zou, L., von Mering, C., PCAWG Drivers Functional, PCAWG Consortium 2020; 3 (1): 56

    Abstract

    Long non-coding RNAs (lncRNAs) are a growing focus of cancer genomics studies, creating the need for a resource of lncRNAs with validated cancer roles. Furthermore, it remains debated whether mutated lncRNAs can drive tumorigenesis, and whether such functions could be conserved during evolution. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, we introduce the Cancer LncRNA Census (CLC), a compilation of 122 GENCODE lncRNAs with causal roles in cancer phenotypes. In contrast to existing databases, CLC requires strong functional or genetic evidence. CLC genes are enriched amongst driver genes predicted from somatic mutations, and display characteristic genomic features. Strikingly, CLC genes are enriched for driver mutations from unbiased, genome-wide transposon-mutagenesis screens in mice. We identified 10 tumour-causing mutations in orthologues of 8 lncRNAs, including LINC-PINT and NEAT1, but not MALAT1. Thus CLC represents a dataset of high-confidence cancer lncRNAs. Mutagenesis maps are a novel means for identifying deeply-conserved roles of lncRNAs in tumorigenesis.

    View details for DOI 10.1038/s42003-019-0741-7

    View details for Web of Science ID 000512019200002

    View details for PubMedID 32024996

    View details for PubMedCentralID PMC7002399

  • Analyses of non-coding somatic drivers in 2,658cancer whole genomes. Nature Rheinbay, E., Nielsen, M. M., Abascal, F., Wala, J. A., Shapira, O., Tiao, G., Hornshoj, H., Hess, J. M., Juul, R. I., Lin, Z., Feuerbach, L., Sabarinathan, R., Madsen, T., Kim, J., Mularoni, L., Shuai, S., Lanzos, A., Herrmann, C., Maruvka, Y. E., Shen, C., Amin, S. B., Bandopadhayay, P., Bertl, J., Boroevich, K. A., Busanovich, J., Carlevaro-Fita, J., Chakravarty, D., Chan, C. W., Craft, D., Dhingra, P., Diamanti, K., Fonseca, N. A., Gonzalez-Perez, A., Guo, Q., Hamilton, M. P., Haradhvala, N. J., Hong, C., Isaev, K., Johnson, T. A., Juul, M., Kahles, A., Kahraman, A., Kim, Y., Komorowski, J., Kumar, K., Kumar, S., Lee, D., Lehmann, K., Li, Y., Liu, E. M., Lochovsky, L., Park, K., Pich, O., Roberts, N. D., Saksena, G., Schumacher, S. E., Sidiropoulos, N., Sieverling, L., Sinnott-Armstrong, N., Stewart, C., Tamborero, D., Tubio, J. M., Umer, H. M., Uuskula-Reimand, L., Wadelius, C., Wadi, L., Yao, X., Zhang, C., Zhang, J., Haber, J. E., Hobolth, A., Imielinski, M., Kellis, M., Lawrence, M. S., von Mering, C., Nakagawa, H., Raphael, B. J., Rubin, M. A., Sander, C., Stein, L. D., Stuart, J. M., Tsunoda, T., Wheeler, D. A., Johnson, R., Reimand, J., Gerstein, M., Khurana, E., Campbell, P. J., Lopez-Bigas, N., PCAWG Drivers and Functional Interpretation Working Group, PCAWG Structural Variation Working Group, Weischenfeldt, J., Beroukhim, R., Martincorena, I., Pedersen, J. S., Getz, G., PCAWG Consortium, Abascal, F., Amin, S. B., Bader, G. D., Bandopadhayay, P., Barenboim, J., Beroukhim, R., Bertl, J., Boroevich, K. A., Brunak, S., Campbell, P. J., Carlevaro-Fita, J., Chakravarty, D., Chan, C. W., Chen, K., Choi, J. K., Deu-Pons, J., Dhingra, P., Diamanti, K., Feuerbach, L., Fink, J. L., Fonseca, N. A., Frigola, J., Gambacorti-Passerini, C., Garsed, D. W., Gerstein, M., Getz, G., Guo, Q., Gut, I. G., Haan, D., Hamilton, M. P., Haradhvala, N. J., Harmanci, A. O., Helmy, M., Herrmann, C., Hess, J. M., Hobolth, A., Hodzic, E., Hong, C., Hornshoj, H., Isaev, K., Izarzugaza, J. M., Johnson, R., Johnson, T. A., Juul, M., Juul, R. I., Kahles, A., Kahraman, A., Kellis, M., Khurana, E., Kim, J., Kim, J. K., Kim, Y., Komorowski, J., Korbel, J. O., Kumar, S., Lanzos, A., Larsson, E., Lawrence, M. S., Lee, D., Lehmann, K., Li, S., Li, X., Lin, Z., Liu, E. M., Lochovsky, L., Lou, S., Madsen, T., Marchal, K., Martincorena, I., Martinez-Fundichely, A., Maruvka, Y. E., McGillivray, P. D., Meyerson, W., Muinos, F., Mularoni, L., Nakagawa, H., Nielsen, M. M., Paczkowska, M., Park, K., Park, K., Pedersen, J. S., Pons, T., Pulido-Tamayo, S., Raphael, B. J., Reimand, J., Reyes-Salazar, I., Reyna, M. A., Rheinbay, E., Rubin, M. A., Rubio-Perez, C., Sahinalp, S. C., Saksena, G., Salichos, L., Sander, C., Schumacher, S. E., Shackleton, M., Shapira, O., Shen, C., Shrestha, R., Shuai, S., Sidiropoulos, N., Sieverling, L., Sinnott-Armstrong, N., Stein, L. D., Stuart, J. M., Tamborero, D., Tiao, G., Tsunoda, T., Umer, H. M., Uuskula-Reimand, L., Valencia, A., Vazquez, M., Verbeke, L. P., Wadelius, C., Wadi, L., Wang, J., Warrell, J., Waszak, S. M., Weischenfeldt, J., Wheeler, D. A., Wu, G., Yu, J., Zhang, J., Zhang, X., Zhang, Y., Zhao, Z., Zou, L., von Mering, C., Akdemir, K. C., Alvarez, E. G., Baez-Ortega, A., Beroukhim, R., Boutros, P. C., Bowtell, D. D., Brors, B., Burns, K. H., Busanovich, J., Campbell, P. J., Chan, K., Chen, K., Cortes-Ciriano, I., Dueso-Barroso, A., Dunford, A. J., Edwards, P. A., Estivill, X., Etemadmoghadam, D., Feuerbach, L., Fink, J. L., Frenkel-Morgenstern, M., Garsed, D. W., Gerstein, M., Gordenin, D. A., Haan, D., Haber, J. E., Hess, J. M., Hutter, B., Imielinski, M., Jones, D. T., Ju, Y. S., Kazanov, M. D., Klimczak, L. J., Koh, Y., Korbel, J. O., Kumar, K., Lee, E. A., Lee, J. J., Li, Y., Lynch, A. G., Macintyre, G., Markowetz, F., Martincorena, I., Martinez-Fundichely, A., Meyerson, M., Miyano, S., Nakagawa, H., Navarro, F. C., Ossowski, S., Park, P. J., Pearson, J. V., Puiggros, M., Rippe, K., Roberts, N. D., Roberts, S. A., Rodriguez-Martin, B., Schumacher, S. E., Scully, R., Shackleton, M., Sidiropoulos, N., Sieverling, L., Stewart, C., Torrents, D., Tubio, J. M., Villasante, I., Waddell, N., Wala, J. A., Weischenfeldt, J., Yang, L., Yao, X., Yoon, S., Zamora, J., Zhang, C. 2020; 578 (7793): 102–11

    Abstract

    The discovery of drivers of cancer has traditionally focused on protein-coding genes1-4. Here we present analyses of driver point mutations and structural variants in non-coding regions across 2,658genomes from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium5 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). For point mutations, we developed a statistically rigorous strategy for combining significance levels from multiple methods of driver discovery that overcomes the limitations of individual methods. For structural variants, we present two methods of driver discovery, and identify regions that are significantly affected by recurrent breakpoints and recurrent somatic juxtapositions. Our analyses confirm previously reported drivers6,7, raise doubts about others and identify novel candidates, including point mutations in the 5' region of TP53, in the 3' untranslated regions of NFKBIZ and TOB1, focal deletions in BRD4 and rearrangements in the loci of AKR1C genes. We show that althoughpoint mutations and structural variants that drive cancer are less frequent in non-coding genes and regulatory sequences than in protein-coding genes, additional examples of these drivers will be found as more cancer genomes become available.

    View details for DOI 10.1038/s41586-020-1965-x

    View details for PubMedID 32025015

  • MiR-1271-5p: An AR-modulatory microRNA with a distinct role in prostate cancer progression, through SND1 and MORF4L1 interaction. Kalofonou, F., Leach, D., Hamilton, M., Mcguire, S., Fletcher, C., Waxman, J., Bevan, C. L. AMER SOC CLINICAL ONCOLOGY. 2019

    View details for DOI 10.1200/JCO.2019.37.15_suppl.e16562

    View details for Web of Science ID 000487345801592