Showing papers by "Jay Bowen published in 2021"
National Institutes of Health1, Broad Institute2, Academy of Medical Sciences, United Kingdom3, Nvidia4, Leidos5, University of North Carolina at Chapel Hill6, Imperial College London7, Ohio State University8, Nationwide Children's Hospital9, Radiation Effects Research Foundation10, Harvard University11
TL;DR: In this paper, the authors analyzed genomic, transcriptomic, and epigenomic characteristics of 440 Papillary thyroid carcinoma (PTC) from Ukraine (from 359 individuals with estimated childhood 131I exposure and 81 unexposed children born after 1986).
Abstract: The 1986 Chernobyl nuclear power plant accident increased papillary thyroid carcinoma (PTC) incidence in surrounding regions, particularly for radioactive iodine (131I)-exposed children. We analyzed genomic, transcriptomic, and epigenomic characteristics of 440 PTCs from Ukraine (from 359 individuals with estimated childhood 131I exposure and 81 unexposed children born after 1986). PTCs displayed radiation dose-dependent enrichment of fusion drivers, nearly all in the mitogen-activated protein kinase pathway, and increases in small deletions and simple/balanced structural variants that were clonal and bore hallmarks of nonhomologous end-joining repair. Radiation-related genomic alterations were more pronounced for individuals who were younger at exposure. Transcriptomic and epigenomic features were strongly associated with driver events but not radiation dose. Our results point to DNA double-strand breaks as early carcinogenic events that subsequently enable PTC growth after environmental radiation exposure.
61 citations
Baylor College of Medicine1, Van Andel Institute2, University of North Carolina at Chapel Hill3, University of Texas MD Anderson Cancer Center4, Foundation Medicine5, Catalan Institution for Research and Advanced Studies6, University of Arkansas for Medical Sciences7, Nationwide Children's Hospital8
TL;DR: Analysis of tumor biopsies from an unbiased cohort of 111 exceptional responder patients revealed synthetic lethal relationships that may be exploited therapeutically and rare genetic lesions that favor therapeutic success, while also providing a wealth of testable hypotheses regarding oncogenic mechanisms that may influence the response to cancer therapy.
55 citations
TL;DR: In this paper, the authors evaluated the feasibility of identifying exceptional responders retrospectively, obtaining pre-exceptional response treatment tumor tissues, and analyzing them with state-of-the-art molecular analysis tools to identify potential molecular explanations for responses.
Abstract: Background Tumor molecular profiling from patients experiencing exceptional responses to systemic therapy may provide insights into cancer biology and improve treatment tailoring. This pilot study evaluates the feasibility of identifying exceptional responders retrospectively, obtaining pre-exceptional response treatment tumor tissues, and analyzing them with state-of-the-art molecular analysis tools to identify potential molecular explanations for responses. Methods Exceptional response was defined as partial (PR) or complete (CR) response to a systemic treatment with population PR or CR rate less than 10% or an unusually long response (eg, duration >3 times published median). Cases proposed by patients' clinicians were reviewed by clinical and translational experts. Tumor and normal tissue (if possible) were profiled with whole exome sequencing and, if possible, targeted deep sequencing, RNA sequencing, methylation arrays, and immunohistochemistry. Potential germline mutations were tracked for relevance to disease. Results Cases reflected a variety of tumors and standard and investigational treatments. Of 520 cases, 476 (91.5%) were accepted for further review, and 222 of 476 (46.6%) proposed cases met requirements as exceptional responders. Clinical data were obtained from 168 of 222 cases (75.7%). Tumor was provided from 130 of 168 cases (77.4%). Of 117 of the 130 (90.0%) cases with sufficient nucleic acids, 109 (93.2%) were successfully analyzed; 6 patients had potentially actionable germline mutations. Conclusion Exceptional responses occur with standard and investigational treatment. Retrospective identification of exceptional responders, accessioning, and sequencing of pretreatment archived tissue is feasible. Data from molecular analyses of tumors, particularly when combining results from patients who received similar treatments, may elucidate molecular bases for exceptional responses.
16 citations