Whole Genome Sequencing Reveals Elevated Tumor Mutational Burden and Initiating Driver Mutations in African Men with Treatment-Naive, High-Risk Prostate Cancer

African American men are more likely than any other racial group to die from prostate cancer. The contribution of acquired genomic variation to this racial disparity is largely unknown, as genomic from Africa is lacking. Here we performed the first tumor-normal paired deep whole-genome sequencing for Africa. A direct study-matched comparison between African- and European-derived, treatment-naïve, high-risk prostate tumors for 15 cases allowed for further comparative analyses of existing data. Excluding a single hyper-mutated tumor with 55 mutations per megabase, we observed a 1.8-fold increase in small somatic variants in African- versus European-derived tumors (P-value = 1.02e-04), rising to 4-fold when compared with published tumor-matched data. Furthermore, we observed an increase in oncogenic driver mutations in African tumors (P-value = 2.92e-03); roughly 30% of impacted genes were novel to prostate cancer, and 79% of recurrent driver mutations appeared early in tumorigenesis. Although complex genomic rearrangements were less frequent in African tumors, we describe a uniquely hyper-duplicated tumor impacting 149 transposable elements. Comparable to African Americans, ERG fusions and PIK3CA mutations were absent and PTEN loss less frequent. CCND1 and MYC were frequently gained, with somatic copy number changes more likely to occur late in tumorigenesis. In addition to traditional prostate cancer gene pathways, genes regulating calcium ion-ATPase signal transduction were disrupted in African tumors. Although preliminary, our results suggest that further validation and investigation into the potential implications for elevated tumor mutational burden and tumor-initiating mutations in clinically unfavorable prostate cancer can improve patient outcomes in Africa.

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