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Mutational Landscape of the Y Chromosome and Prostate Cancer
[Technical Report, Final Report]
SLOAN-KETTERING INST FOR CANCER RESEARCH NEW YORK
Pagination or Media Count:
Mortality from prostate cancer PC, an estimated 33,330 deaths in 2020, is associated with developmentof aggressive and treatment-insensitive metastatic castration-resistant prostate cancer mCRPC. We willinvestigate the status and role of Y chromosome ChrY genes in regulating drug sensitivity and mCRPCdevelopment and progression. Though ChrY loss in men is associated with increased risk of disease andmortality, the role of ChrY genes in regulating PC progression is poorly understood. To investigate theclinical impact of ChrY gene expression, we developed new methodology to analyze mutational variants ofChrY genes in PC patient cohorts, previously unsuccessful due to the high number of repetitive sequencesand paralog families. Using a custom reference for each paralog family, our method increased ChrY readdepth coverage to be on par with whole-exome sequencing allowing for normaltumor variant calling. Wealso generated the first CRISPRCas9 library targeting human ChrY to further understand the role ofindividual ChrY genes in regulating antiandrogen treatment sensitivity and mCRPC development in PCmodels in vitro and in vivo. This multifaceted approach will potentially identify predictive markers fortreatment sensitivity based on ChrY. These markers will allow for development of tailored therapies andserve as targets for drug development.
[A, Approved For Public Release]