Grant Number:	3R01CA259200-04S6 Interpret this number
Primary Investigator:	Rebbeck, Timothy
Organization:	Dana-Farber Cancer Inst
Project Title:	Genomic and Genomic Variation in Prostate Cancer
Fiscal Year:	2025

There is consistent evidence that germline genetics and tumor (somatic) genomics have a substantial impact on the incidence (occurrence) of prostate cancer. Prostate cancer incidence has one of the highest heritabilities of any common cancer. Over 450 low penetrance genetic variants have been identified by genome-wide association studies, and numerous high penetrance pathogenic variants are established to cause prostate cancer. In addition, there is growing evidence for substantial variation in the mutational landscape of prostate tumors. These pathways include known carcinogenesis mechanisms such as DNA damage repair, immunological surveillance, and steroid hormone metabolism. Molecularly-defined tumor subtypes are emerging that likely confer differences in prostate cancer progression and treatment response. These observations support the hypothesis that genetic and genomic factors influence prostate cancer incidence and tumor aggressiveness. Limited genetic variation to date has been available to inform the optimal clinical translation of genetic and genomic features for American men with prostate cancer. It has been demonstrated that research that does not account for the full range of genotypic or genomic variation leads to genetic misdiagnoses and other errors that result in sub-optimal clinical translation of this information. Thus, to inform the genetic and genomic basis of prostate cancer, we propose to address the following Aims: Aim 1: Identify common genetic variants associated with prostate cancer aggressiveness; Aim 2: Define histopathological features of prostate tumors that correlate with germline genetic and tumor somatic genomic variation; and Aim 3: Evaluate molecular signatures and subtypes in prostate tumors to improve clinical translation of genetic and genomic data. Our research will combine data from multiple sources to address the critical need for optimized variability in cancer genomics data. Maximal variation in genetic and genomic data will not only improve our understanding of genomic contributors to prostate cancer etiology and also aid in the development and translation of cancer genomic tools, reduce the potential for errors in determining pathogenicity of genetic susceptibility variants, and improve interpretation of cancer risk assessment for Americans. we will improve the ability to predict which American men will benefit from risk-stratified prostate cancer prevention, early detection, and precision medicine therapeutics. We have constructed these resources to integrate directly with existing publicly available databases, such as TCGA/ICGC and GENIE, to ensure our data can be readily compared with data from other sources. Our data will also include deep pathology, clinical and risk factor annotation, largely unavailable in current public datasets, to provide a fuller potential to understand of prostate cancer etiology and progression.





None. See parent grant details.