Rare pathogenic structural variants show potential to enhance prostate cancer germline testing for African men

TL;DR

This study shows that rare structural variants may improve prostate cancer genetic testing for African men, who are currently underrepresented in genomic data.

Contribution

The study identifies African-specific pathogenic structural variants in prostate cancer that are not well captured in current germline testing.

Findings

15 potentially pathogenic structural variants were identified in 12.4% of African and 7.0% of European prostate cancer patients.

African-specific loss-of-function genes like MLH1 and BARD1 were highlighted as important in prostate cancer.

Rare kilo-to-mega-base variants may contribute to prostate cancer disparities in African populations.

Abstract

Prostate cancer (PCa) is highly heritable, with men of African ancestry at greatest risk and associated lethality. Lack of representation in genomic data means germline testing guidelines exclude for African men. Established that structural variations (SVs) are major contributors to human disease and prostate tumourigenesis, their role is under-appreciated in familial and therapeutic testing. Utilising a clinico-methodologically matched African (n = 113) versus European (n = 57) deep-sequenced PCa resource, we interrogated 42,966 high-quality germline SVs using a best-fit pathogenicity prediction workflow. We identified 15 potentially pathogenic SVs representing 12.4% African and 7.0% European patients, of which 72% and 86% met germline testing standard-of-care recommendations, respectively. Notable African-specific loss-of-function gene candidates include DNA damage repair MLH1 and BARD1 and tumour suppressors FOXP1, WASF1 and RB1. Representing only a fraction of the vast African diaspora, this study raises considerations with respect to the contribution of kilo-to-mega-base rare variants to PCa pathogenicity and African associated disparity.

Figures