The Germline and Somatic Origins of Prostate Cancer Heterogeneity

Newly diagnosed prostate cancers differ dramatically in mutational composition and lethality. The most accurate clinical predictor of lethality is tumor tissue architecture, quantified as tumor grade. To interrogate the evolutionary origins of prostate cancer heterogeneity, we analyzed 666 prostate tumor whole genomes. We identified a compendium of 223 recurrently mutated driver regions, most influencing downstream mutational processes and gene expression. We identified and validated individual germline variants that predispose tumors to acquire specific somatic driver mutations: these explain heterogeneity in disease presentation and ancestry differences. High-grade tumors have a superset of the drivers in lower-grade tumors, including increased frequency of BRCA2 and MYC mutations. Grade-associated driver mutations occur early in tumor evolution, and their earlier occurrence strongly predicts cancer relapse and metastasis. Our data suggest high-and low-grade prostate tumors both emerge from a common premalignant field, influenced by germline genomic context and stochastic mutation timing. Significance: This study uncovered 223 recurrently mutated driver regions using the largest cohort of prostate tumors to date. It reveals associations between germline SNPs, somatic drivers, and tumor aggression, offering significant insights into how prostate tumor evolution is shaped by germline factors and the timing of somatic mutations.