The Genetic Origin of Hereditary Prostate Cancer

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Prostate cancer is the most common cancer among Veterans. Nationally, its mortality rate is 76% that of breast cancer; one in 41 men will die of it. National Comprehensive Cancer Network Guidelines for precision prostate cancer care have incorporated tumor sequencing for men with advanced-stage prostate cancer, and germline sequencing of men with a family history of prostate cancer. Its purpose is to discern inherited as well as somatic drivers to guide precision therapy, though also potentially uncovering familial cancer risks. But the knowledge base to guide prognostic and therapeutic decision-making in prostate cancer remains very limiting. Even though prostate cancer has the greatest heritable risk of all common cancers, the causes of nearly 90% of its inherited forms remain unknown. In contrast to breast and other common cancers, the broad diversity of hereditary prostate cancer's causes has impeded traditional pedigree-based investigation by linkage. The goal of this study is to further elucidate diverse causes of hereditary prostate cancer using a novel, alternative familial case-control study design. We compare independent cases, each with a strong family history of prostate cancer, to screened controls, each with a negative family history of prostate cancer. Our Aims capitalize upon dense genetic data to identify cases that share a given disease gene inherited from a common distant ancestor, even though genealogical relationships among them are not known. We identify disease genes by discerning excess sharing of ancestral genomic segments among cases, reconstructing haplotypes harboring mutations with strong risk of prostate cancer, and discerning correlated regional genetic variants and underlying candidate causal mutations. We introduce a novel algorithm to identify sentinel variants best detecting the independent risk signals, and forming a clinically predictive model. We further delineate which genetic loci are responsible for the early age of diagnosis characterizing familial disease, some also impacting aggressiveness. We employ replication across independent familial case-control study populations to discern true from false positive observations, and we evaluate additional existing case-control and biobank data sets to generalize pertinent observations. This study will improve the knowledge base for precision oncology and familial cancer care of Veterans.