Abstract
Prostate cancer (PCa) is marked by significant ancestral bias, with African men disproportionately impacted. However, genome profiling studies have yet to explore the mutational landscape and disparity contribution of the male-determining Y chromosome. Using a cohort of 106 African and 57 European PCa cases, biased toward aggressive presenting primary disease, we performed complete Y chromosome interrogation for inherited and somatic variance. Capturing unexplored early-diverged Y-haplogroup substructure, while European men are 3.1-fold more likely to present with a rare potentially deleterious germline variant, a higher proportion of African patients acquired Y chromosome tumorigenic events (26.4% African, 14% European). While somatic copy number alterations were universally more common to aggressive tumors, besides shared alterations impacting DDX3Y and USP9Y, African derived tumors were prone to somatic losses associated with KDM5D, PCDH11Y, and RBMY. This much-needed African inclusive study alludes to possible Y chromosome contribution, at least in part, to treatment resistance and worsened mortality rates in African men.
| Original language | English |
|---|---|
| Article number | 112437 |
| Journal | iScience |
| Volume | 28 |
| Issue number | 5 |
| Early online date | 15 Apr 2025 |
| DOIs | |
| Publication status | Published - 16 May 2025 |
| Externally published | Yes |
Data Availability Statement
Data: DNA sequence data have been deposited at the European Genome-Phenome Archive (EGA), and the accession number is listed in the key resources table. They are available upon request if access is granted. This paper uses existing, publicly available data from gnomAD v3.1.2. The link to the dataset is listed in the key resources table.•
Code: This paper does not report original code.
•
All other items: Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request
Acknowledgements
We acknowledge, most importantly, the patients and the clinical staff who contributed to the Southern African Prostate Cancer Study (SAPCS) and the St Vincent’s Hospital Sydney resources in South Africa and Australia, respectively, as well as all the additional authors who contributed to generating or interrogating the published whole genome data resource. We acknowledge the Sydney Informatic Hub at the University of Sydney for providing critical computational infrastructure.Funding
Genomic sequencing was supported by the National Health and Medical Research Council (NHMRC) of Australia through a Project Grant (APP1165762 to V.M.H.) and Ideas Grants (APP2001098 to V.M.H. and M.S.R.B.; APP2010551 to V.M.H.). Further analytics was supported by a U.S.A. Congressionally Directed Medical Research Programs (CDMRP) Prostate Cancer Research Program (PCRP) HEROIC Consortium Award (PC210168 and PC230673, HEROIC PCaPH Africa1K to V.M.H. and M.S.R.B., which includes co-leads Professors Gail Prins, University of Illinois at Chicago, U.S.A., and Mungai Peter Ngugi, University of Nairobi, Kenya), a U.S.A. National Institute of Health (NIH) National Cancer Institute (NCI) Award (1R01CA285772-01 to V.M.H.) and a U.S.A. Prostate Cancer Foundation (PCF) Challenge Award (2023CHAL4150 to V.M.H.). V.M.H. was further supported by the Petre Foundation via the University of Sydney Foundation, Australia.
Keywords
- Cancer
- Human genetics
- Sequence analysis
ASJC Scopus subject areas
- General
