Leveraging whole-exome sequence data from diverse biobanks and cohorts to study rare coding variation in prostate cancer

Abstract

There is strong evidence that prostate cancer (PCa) is a heritable phenotype. In addition to greater risk observed

in men with a family history of PCa, genome-wide association studies (GWAS) have identified over 400 common

independent risk variants, which explain ~40% of the familial risk. It is increasingly recognized that much of the

unknown heritability for PCa may also be due to variants of low minor allele frequency (500,000 controls within biobanks and cohorts in the US and UK and conduct exome-wide

analyses of overall PCa and aggressive disease phenotypes. In Aim 2, we will examine the combined effect of

rare coding variants and a polygenic risk score (PRS) on risk of overall PCa and aggressive disease and estimate

absolute risks for the combined effects of rare coding variants and PRS in prospective biobanks and cohorts

across populations. In Aim 3, we will integrate somatic tumor and germline variation data to inform genes and

biological pathways involved in PCa and aggressive disease. For this Aim, we have assembled a somatic

resource of >7,000 PCa patients with germline exome/PRS data and somatic mutation profiling from WES and

WGS studies, including >2,000 with transcriptomic data. We expect this study to provide the most comprehensive

and well-powered examination of rare coding variation in PCa across populations to date. Findings from this

study will have immediate clinical translation by informing personalized risk prediction and the development of

novel risk-based screening strategies for overall and aggressive PCa. Integrating germline and somatic data will

also define biological mechanisms that may be clinically important for understanding how to treat and prevent

PCa and lethal disease across populations.