Genetic predictors of prostate cancer survival

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PROJECT SUMMARY/ABSTRACT The underlying scientific premise of the parent grant is that the risk factors and mechanisms that drive prostate cancer development likely differ from those that drive prostate cancer mortality. Here, the proposed supplement project seeks to understand whether race-specific risk factor associations and mechanisms contribute to long- standing, poorly understood excess prostate cancer disease burden among Black men. The proposed project focuses on prostate cancer risk in Black men in this context through examination of a risk factor – vitamin D – previously found to be associated with an increased risk of prostate cancer incidence, but a decreased risk of prostate cancer mortality based primarily on data from White men. Although the complex relationship of vitamin D with prostate cancer has been well-studied in white men, there is limited research focused on elucidating this relationship among Black men. This is notable given the well-established: 1) higher risk of developing and dying from prostate cancer for Black compared to White men; 2) Black-White differences in vitamin D profiles defined by circulating concentrations of 25-hydroxyvitamin D (25(OH)D) – the metabolite used to define vitamin D status – with chronically low concentrations in Black populations, and Black-White differences in genetic variants in multiple vitamin D-related genes; and 3) the identification of genetic variants in vitamin D related genes associated with prostate cancer risk. The persistent gaps in the vitamin D-prostate cancer research focused on Black men likely perpetuate existing disparities as vitamin D, a modifiable factor, is known to influence several molecular processes that drive carcinogenesis in the prostate. This knowledge gap highlights the importance of cancer health disparities research and research translation in reducing the overall cancer burden. Given this, the proposed project will implement the gene-centered approach used in the parent grant to determine whether and how genetic variants (single nucleotide polymorphisms (SNPs)) in genes from the vitamin D pathway influence prostate cancer in an understudied group at high risk for both vitamin D deficiency and prostate cancer. Specifically, the proposed supplement project examines the role of genes involved in vitamin D synthesis (CYP27A1 and CYP27B1), transport (GC), activity (VDR and RXR), and metabolism (CYP24A1) in relation to prostate cancer risk (Aim #1) and mortality (Aim #2). Additionally, both aims will include validation analyses of the identified SNP associations in an independent sample of Black men (Aims 1b and 2b), and in silico analyses to identify the functional basis for the identified SNP associations based on normal (Aim 1c) and malignant prostate tissue (Aim 2c). This proposal is a distinctly valuable career development opportunity for the candidate as it will provide mentorship and training in cancer genomics and genetic epidemiology, a new area for the candidate. This project also allows the candidate to leverage the uniquely rich resources and large cohorts assembled by the parent grant to address a considerable gap in the vitamin D-prostate cancer association literature by improving our understanding of the role of vitamin D in an understudied population of Black men. . 1