Mutational Landscape of the Y Chromosome and Prostate Cancer
Technical Report,15 Jun 2018,14 Jun 2019
Sloan Kettering Institute for Cancer Research New York United States
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Mortality from prostate cancer PC, an estimated 30,000 deaths in 2019, is associated with development of aggressive and treatment-insensitive metastatic castration-resistant prostate cancer mCRPC. We will investigate the status and role of Y chromosome ChrY genes in regulating drug sensitivity and mCRPC development and progression. Though ChrY loss in men is associated with increased risk of disease and mortality, the role of ChrY genes in regulating PC progression is poorly understood. To investigate the clinical impact of ChrY gene expression, we developed new methodology to analyze mutational variants of ChrY genes in PC patient cohorts, previously unsuccessful due to the high number of repetitive sequences and paralog families. Using a custom reference for each paralog family, our method increased ChrY read depth coverage to be on par with whole-exome sequencing allowing for normaltumor variant calling. We also generated the first CRISPRCas9 library targeting human ChrY to further understand the role of individual ChrY genes in regulating antiandrogen treatment sensitivity and mCRPC development in PC models in vitro and in vivo. This multifaceted approach will potentially identify predictive markers for treatment sensitivity based on ChrY. These markers will allow for development of tailored therapies and serve as targets for drug development.
- Medicine and Medical Research