PGSG Seminar Series- Burcu Darst

Prostate cancer (PCa) is a highly heritable disease with large disparities in incidence rates across populations. To improve our understanding of genetic risk of PCa, we conducted the largest and most diverse PCa GWAS meta-analysis to date with over 107,000 cases and 127,000 controls from the Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome (PRACTICAL) consortium. Results from this analysis led to the identification of 86 novel PCa risk variants, bringing the total known risk variants to 269, and the construction of a trans-ancestry polygenic risk score (PRS) that is highly predictive of PCa risk across diverse populations. Integrating this PRS with whole-exome sequencing data from ~81,000 men from the UK Biobank, we found that PCa risk conveyed by carrier status for rare pathogenic variants varies widely depending on an individual’s PRS, suggesting that combining the PRS with carrier status would substantially improve risk estimates. Further, to understand the biological mechanisms impacted by genetic risk of PCa, we conducted integrative analyses of the PRS and serum metabolomics in 691 African ancestry men from the Multiethnic Cohort and observed evidence of the PRS impacting levels of sphingolipids and particular amino acids. These findings support the role of germline variation contributing to health disparities in PCa risk, with the PRS offering an approach for personalized risk prediction across populations and informing the biological mechanisms underlying PCa risk.

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Topic: PGSG Seminar Series

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