Whole Exome Sequencing of Nigerian Prostate Tumors from the Prostate Cancer Transatlantic Consortium (CaPTC) Reveals DNA Repair Genes Associated with African Ancestry

Abstract

In this study, we used whole-exome sequencing of a cohort of 45 advanced-stage, treatment-naive Nigerian (NG) primary prostate cancer (PCa) tumors and 11 unmatched non-tumor tissues to compare genomic alterations with African American (AA) and European American (EA) TCGA PCa. NG samples were collected from 6 sites in central and southwest Nigeria. After whole-exome sequencing, samples were processed using GATK best practices. BRCA1 (100%), BARD1 (45%), BRCA2 (27%), and PMS2(18%) had germline alterations in at least two NG non-tumor samples. Across 111 germline variants, the AA cohort reflected a pattern [BRCA1 (68%), BARD1 (34%), BRCA2 (28%), and PMS2 (16%)] similar to NG samples. Of the most frequently mutated genes, BRCA1 showed a statistically (p ≤ 0.05) higher germline mutation frequency in men of African ancestry (MAA) and increasing variant frequency with increased African ancestry. Disaggregating gene level mutation frequencies by variants revealed both ancestry-linked and NG-specific germline variant patterns. Driven by rs799917 (T>C), BRCA1 showed an increasing mutation frequency as African admixture increased. BRCA2_rs11571831 was present only in MAAs, and BRCA2_rs766173 was elevated in NG men. 133 somatic variants were present in 26 PCa-associated genes within the NG tumor cohort. BRCA2 (27%), APC (20%), ATM (20%), BRCA1 (13%), DNAJC6 (13%), EGFR (13%), MAD1L1 (13%), MLH1 (11%), and PMS2 (11%) showed mutation frequencies > 10%. Compared to TCGA cohorts, NG tumors showed statistically significant elevated frequencies of BRCA2, APC, and BRCA1. The NG cohort variant pattern shared similarities (cosign similarities ≥ 0.734) with COSMIC signatures 5 and 6, and mutated genes showed significant (q < 0.001) GO and functional enrichment in mismatch repair and non-homologous repair deficiency pathways. Here, we showed that alterations in DNA damage response (DDR) genes were higher in NG PCa samples and that a portion of those alterations correlate with African ancestry. Moreover, we identified variants of unknown significance that may contribute to population-specific routes of tumorigenesis and treatment. These results present the most comprehensive characterization of the NG PCa exome to date and highlight the need to increase diversity of study populations.

Heterogeneous genetic architectures and evolutionary genomics of prostate cancer in Sub-Saharan Africa

“…Prior genetic investigations of CaP in Africa have largely been restricted to studies with limited sample sizes. 6, [30][31][32] Thus, there is a clear need to study the genetics of CaP at scale in multiple African populations, while also leveraging the emerging genomics capacity within Africa.…”