Pathogenic Variants in Cancer Predisposition Genes and Prostate Cancer Risk in Men of African Ancestry

Abstract

Purpose: In studies of men of European ancestry, rare pathogenic variants in DNA repair pathway genes have been shown to be associated with risk of aggressive prostate cancer. The contribution of rare coding variation to prostate cancer risk in men of African ancestry has not been established.

Methods: We sequenced a panel of 19 DNA repair and cancer predisposition genes in 2,453 African American and 1,151 Ugandan prostate cancer cases and controls. Rare variants were classified as pathogenic or putatively functionally disruptive and examined in association with prostate cancer risk and disease aggressiveness in gene and pathway-level association analyses.

Results: Pathogenic variants were found in 75 out of 2,098 cases (3.6%) and 31 out of 1,481 controls (2.1%) (OR=1.82, 95% CI=1.19 to 2.79, P=0.0044) with the association being stronger for more aggressive disease phenotypes (OR=3.10, 95% CI=1.54 to 6.23, P=0.0022). The highest risks for aggressive disease were observed with pathogenic variants in the ATM, BRCA2, PALB2 and NBN genes, with odds ratios ranging from ~4 to 15 in the combined study sample of African American and Ugandan men. Rare, non-pathogenic, non-synonymous variants did not have a major impact on risk of overall prostate cancer or disease aggressiveness.

Conclusions: Rare pathogenic variants in DNA repair genes have appreciable effects on risk of aggressive prostate cancer in men of African ancestry. These findings have potential implications for panel testing and risk stratification in this high-risk population.

FIG 1.

Tier 1 variants in genes significantly associated with prostate cancer risk. Each variant (DNA position and resulting amino acid change) in these genes and protein domains is presented by lollipop plots, with the variant type indicated by color. Variants predicted to result in protein truncation or significantly alter the protein sequence (frameshift insertion/deletions, stop codon gained or essential splice site donor/acceptor) and missense variants (nonsynonymous coding, exon start/end codon change) that were reported as pathogenic or likely pathogenic in ClinVar are coded in violet and green, respectively. On the graph of each gene, the x-axis represents the number of amino acid residues, and the y-axis represents the total number of variants identified. Protein domains are also distinguished by color. FAT domain, focal adhesion targeting domain; FATC domain, focal adhesion targeting carboxyterminal domain; FHA, forkhead-associated domain; Nbs1_C, Nijmegen breakage syndrome C-terminal domain.

FIG 2.

Gene burden associations of tier 1 variants with prostate cancer risk by case-control status and strata of disease phenotype. Histograms are used to represent associations of rare pathogenic variants in ATM, BRCA2, PALB2, and NBN genes with prostate cancer risk and aggressiveness in (A) African Americans and Ugandans, (B) African Americans only, and (C) Ugandans only. In each plot, the x-axis reflects the genes and counts of individuals by subgroup, and the y-axis reflects the burden frequency for each subgroup. Numbers above the bars represent risk estimates for cases and aggressive phenotypes compared with controls, with stars indicating the strength of association (P value). Case-control status and strata of disease phenotype are distinguished by color. (*) .05 < P ≤ .1; (**) .01 < P ≤ .05; (***) .001 < P ≤ .01; (****) P ≤ .001.