Family RESPOND: Defining the Genetic Basis of Prostate Cancer Risk in African American Families

It has been estimated that more than 50% of prostate cancer (PCa) is inherited, with studies suggesting that both rare, moderate- to high-penetrant pathogenic variants (PVs) as well as more common variants of lower penetrance are important in explaining inherited susceptibility. Evidence to support this includes men with familial or hereditary PCa are at an increased risk for being diagnosed with PCa, and notably more likely to be diagnosed with aggressive clinical features. Rare mutations in DNA repair genes have been implicated in risk for multiple cancers including PCa, and screening for these mutations can determine eligibility for systemic therapies in the metastatic setting. Common genetic variants have also been demonstrated to play a critical role in PCa susceptibility, with polygenic risk scores (PRS) used to identify men with substantially elevated lifetime risks of overall PCa and aggressive disease. Unfortunately, studies investigating the genetic basis underlying familial aggregation of PCa in men of African ancestry have lagged behind those in men of European descent. While the PRS has shown consistent risk estimation across populations, we and others have found that the prevalence and spectrum of rare PVs in the African American (AA) population may be different than in populations of European ancestry. Integrating gene panel testing and PRS has the potential to provide men with PCa with more accurate information about genetically-informed treatment, risk for second cancers, and for unaffected relatives within the family, future cancer risk. The proposed investigation aims to define the genetic factors underlying familial PCa in AA men and to develop risk prediction models for AA men that incorporate the independent and combined effects of PRS, PVs and family history of PCa. To accomplish this, we will leverage existing genetic data for 24,000 unselected AA PCa cases and controls, which includes the RESPOND cohort, a landmark study of over 12,600 AA PCa cases identified through population-based registries from across the United States, including 7,500 with DNA and genetic information [whole-genome sequence (WGS) data], and 45% reporting a first- and/or second-degree FH of PCa. For this study, we will enroll additional eligible first- and second-degree affected and unaffected family members identified through RESPOND probands to study genetic factors that contribute to familial risk of PCa in AA men (Aim 1). Determine the relative contribution of germline variants to familial clustering of PCa and aggressive disease characteristics within unselected cases and controls (Aim 2) and in AA families in RESPOND (Aim 3). Simultaneously, we will develop and test a risk prediction tool for PCa specifically designed for AA men, that incorporates information on the joint impact of rare variants, PRS, and familial risk in AA families (Aim 4). Through this work, we aim to define the prevalence and spectrum of genetic variants in AA men that contribute to familial PCa and develop a PCa risk prediction tool specifically designed for AA men that can be used for counseling AA men about their risk and as a tool for future risk-stratified screening approaches.