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.

Context summary:

This is the first study aimed to investigate the contribution of rare pathogenic and non-pathogenic coding variation in DNA repair genes to risk of prostate cancer and aggressive disease specifically in men of African ancestry. Rare pathogenic variants in BRCA2, ATM, PALB2 and NBN were significantly associated with high risk of aggressive disease. In addition, we found a substantial number of pathogenic variants that had not been previously reported in major public databases and highlights the importance of sequencing efforts in genetically diverse populations. These findings underscore the clinical relevance of rare pathogenic variants in DNA repair genes in men of African ancestry, which could be used to build better predictive and prognostic gene-based tests to identify men at higher risk of aggressive prostate cancer in this population.