Robert Klein

Ph.D.

Icahn School of Medicine at Mount Sinai

Professor

PLCO (Learn more about this study)

2024-0110

Jun 17, 2024

Genetics of prostate cancer survival in African-American men

Even though most men diagnosed with prostate cancer will not die of the disease, prostate cancer is still the second leading cause of cancer death among men in the United States. While screening for prostate cancer reduces death from disease, this comes at the price of both unnecessary biopsies that reveal no evidence of cancer and treatment of otherwise indolent cancer resulting in unnecessary adverse events. Therefore, there is an unmet need for improved screening tools for prostate cancer. This need is especially important in the African-American population, as African-American men are both more likely to be diagnosed with prostate cancer and to die from the disease if diagnosed. However, to date, most genetic studies on prostate cancer have been conducted in individuals of European ancestry. To address this need, we are conducting an NCI-funded study, “Genetic Predictors of Prostate Cancer Survival”, whose goal is to identify genetic variants associated with survival time in men with prostate cancer. This will be achieved both by testing both imputed gene expression levels, derived from common variants, and pathogenic changes in coding genes, derived from rare coding variants, with survival. As part of the grant, we have approval from the Center for Inherited Disease Research (CIDR) to whole genome sequence germline DNA from African-American prostate cancer patients to identify both common and rare variants that are predictive of outcome in this population. We have obtained over 400 samples from patients from the Durham, NC Veteran's Administration hospital. We are requesting samples from PLCO to increase the power of this study.With the deposition of the whole genome sequencing data in dbGaP, this genetic data will both increase the power and diversity of our studies of the genetics of prostate cancer survival and be of use to others studying genomic influences on disease in African-Americans, both for their data on prostate cancer and as a reference panel for other studies.

1. Identify genes for which genetically controlled expression level changes alter the risk of dying from prostate cancer in African-American men. We hypothesize that common regulatory variants in the prostate will associate with disease-specific
survival time from diagnosis in prostate cancer patients. We will examine the role of common
regulatory variants through a transcriptome-wide association study as well as a genome-wide association study.

2. Identify rare coding variants associated with prostate cancer survival in African-American men. We will identify such associations through kernel-based tests to combine rare variants.

3. Provide a resource for future genetic studies on prostate cancer in African American men by making whole genome sequencing data from the well-annotated PLCO cohort available in dbGaP.