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

Tingting Gong, Jue Jiang, Korawich Uthayopas, M. S. Riana Bornman, Kazzem Gheybi, Phillip D. Stricker, Joachim Weischenfeldt, Shingai B. A. Mutambirwa, Weerachai Jaratlerdsiri and Vanessa M. Hayes ()
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Tingting Gong: University of Sydney
Jue Jiang: University of Sydney
Korawich Uthayopas: University of Sydney
M. S. Riana Bornman: University of Pretoria
Kazzem Gheybi: University of Sydney
Phillip D. Stricker: St Vincent’s Prostate Cancer Research Centre
Joachim Weischenfeldt: Rigshospitalet
Shingai B. A. Mutambirwa: Medunsa
Weerachai Jaratlerdsiri: University of Sydney
Vanessa M. Hayes: University of Sydney

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: 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 Africans. 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 clinico-methodologically matched deep-sequenced whole-genome data for 113 African versus 57 European PCa patients, we interrogate 42,966 high-quality germline SVs using a best-fit pathogenicity prediction workflow. We identify 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.

Date: 2025
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DOI: 10.1038/s41467-025-57312-9

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