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

In this study, we used whole-exome sequencing of a cohort of 45 advanced-stage, treatment-naïve Nigerian (NG) primary prostate cancer tumors and 11 unmatched nontumor tissues to compare genomic mutations with African American (AA) and European American (EA) The Cancer Genome Atlas (TCGA) prostate cancer. NG samples were collected from six 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 nontumor 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 ancestry increased. BRCA2_rs11571831 was present only in MAA, and BRCA2_rs766173 was elevated in NG men. A total of 133 somatic variants were present in 26 prostate cancer–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 with 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 Catalogue of Somatic Mutations in Cancer signatures 5 and 6, and mutated genes showed significant (q < 0.001) gene ontology (GO) and functional enrichment in mismatch repair and non-homologous repair deficiency pathways. Here, we showed that mutations in DNA damage response genes were higher in NG prostate cancer samples and that a portion of those mutations 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 prostate cancer exome to date and highlight the need to increase diversity of study populations.

Significance: MAA have higher rates of prostate cancer incidence and mortality, however, are severely underrepresented in genomic studies. This is the first study utilizing whole-exome sequencing in NG men to identify West African ancestry-linked variant patterns that impact DNA damage repair pathways.

Jason A. White; Ernest T. Kaninjing; Kayode A. Adeniji; Paul Jibrin; John O. Obafunwa; Chidiebere N. Ogo; Faruk Mohammed; Ademola Popoola; Omolara A. Fatiregun; Olabode P. Oluwole; Balasubramanyam Karanam; Isra Elhussin; Stefan Ambs; Wei Tang; Melissa Davis; Paz Polak; Moray J. Campbell; Kathryn R. Brignole; Solomon O. Rotimi; Windy Dean-Colomb; Folake T. Odedina; Damali N. Martin; Clayton Yates

Tuskegee University, Center for Cancer Research, Tuskegee, Alabama; Georgia College & State University, Milledgeville, Georgia; University of Ilorin Teaching Hospital, Nigeria, Ilorin; National Hospital Abuja, Nigeria, Abuja; Lagos State University Teaching Hospital, Ikeja, Lagos, Nigeria; Federal Medical Centre, Abeokuta, Nigeria; Ahmadu Bello University, Zaria Nigeria; University of Abuja, FCT, Nigeria; Molecular Epidemiology Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, NCI, Bethesda, Maryland; Department of Surgery, New York Presbyterian – Weill Cornell Medicine, New York, New York; C2i Genomics, New York, New York; Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, Ohio; University of North Carolina Chapel Hill, North Carolina; Department of Biochemistry, Covenant University, Ota, Nigeria; Piedmont Medical Oncology – Newnan, Newnan, Georgia; Center for Health Equity and Community Engagement Research, Mayo Clinic, Jacksonville, Florida; Division of Cancer Control and Population Sciences, NCI, Rockville, Maryland.

Source: White J., Kaninjing E., Adeniji K. et al. "Whole-exome Sequencing of Nigerian Prostate Tumors from the Prostate Cancer Transatlantic Consortium (CaPTC) Reveals DNA Repair Genes Associated with African Ancestry." Cancer Research Communications. (2022) 2 (9): 1005–1016.

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