Mutational Landscape of the Y Chromosome and Prostate Cancer
Abstract
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 normal/tumor variant calling. We also generated the first CRISPR/Cas9 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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2019
- Accession Number
- AD1094161
Entities
People
- Nikolaus Schultz
- Philip W. Kantoff
Organizations
- Sloan-Kettering Institute