Genome-wide interrogation of structural variation reveals novel African-specific prostate cancer oncogenic drivers.

Autor: Gong T; Ancestry and Health Genomics Laboratory, Charles Perkins Centre, School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW, Australia.; Genomics and Epigenetics Theme, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.; Human Phenome Institute, Fudan University, Shanghai, China., Jaratlerdsiri W; Ancestry and Health Genomics Laboratory, Charles Perkins Centre, School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW, Australia.; Genomics and Epigenetics Theme, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia., Jiang J; Ancestry and Health Genomics Laboratory, Charles Perkins Centre, School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW, Australia.; Genomics and Epigenetics Theme, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia., Willet C; Sydney Informatics Hub, University of Sydney, Sydney, NSW, Australia., Chew T; Sydney Informatics Hub, University of Sydney, Sydney, NSW, Australia., Patrick SM; School of Health Systems and Public Health, University of Pretoria, Pretoria, South Africa., Lyons RJ; Genomics and Epigenetics Theme, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia., Haynes AM; Genomics and Epigenetics Theme, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia., Pasqualim G; Endocrine and Tumor Molecular Biology Laboratory, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.; Laboratory of Genetics, Instituto de Ciências Biológicas, Universidade Federal do Rio Grande, Rio Grande, Brazil., Brum IS; Endocrine and Tumor Molecular Biology Laboratory, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil., Stricker PD; Genomics and Epigenetics Theme, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.; Department of Urology, St. Vincent's Hospital, Darlinghurst, NSW, Australia., Mutambirwa SBA; Department of Urology, Sefako Makgatho Health Science University, Dr George Mukhari Academic Hospital, Medunsa, Ga-Rankuwa, South Africa., Sadsad R; Sydney Informatics Hub, University of Sydney, Sydney, NSW, Australia., Papenfuss AT; Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.; Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia., Bornman RMS; School of Health Systems and Public Health, University of Pretoria, Pretoria, South Africa., Chan EKF; Genomics and Epigenetics Theme, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.; NSW Health Pathology, Sydney, Australia., Hayes VM; Ancestry and Health Genomics Laboratory, Charles Perkins Centre, School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW, Australia. vanessa.hayes@sydney.edu.au.; Genomics and Epigenetics Theme, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia. vanessa.hayes@sydney.edu.au.; School of Health Systems and Public Health, University of Pretoria, Pretoria, South Africa. vanessa.hayes@sydney.edu.au.; Faculty of Health Sciences, University of Limpopo, Turfloop Campus, Mankweng, South Africa. vanessa.hayes@sydney.edu.au.
Jazyk: angličtina
Zdroj: Genome medicine [Genome Med] 2022 Aug 31; Vol. 14 (1), pp. 100. Date of Electronic Publication: 2022 Aug 31.
DOI: 10.1186/s13073-022-01096-w
Abstrakt: Background: African ancestry is a significant risk factor for advanced prostate cancer (PCa). Mortality rates in sub-Saharan Africa are 2.5-fold greater than global averages. However, the region has largely been excluded from the benefits of whole genome interrogation studies. Additionally, while structural variation (SV) is highly prevalent, PCa genomic studies are still biased towards small variant interrogation.
Methods: Using whole genome sequencing and best practice workflows, we performed a comprehensive analysis of SVs for 180 (predominantly Gleason score ≥ 8) prostate tumours derived from 115 African, 61 European and four ancestrally admixed patients. We investigated the landscape and relationship of somatic SVs in driving ethnic disparity (African versus European), with a focus on African men from southern Africa.
Results: Duplication events showed the greatest ethnic disparity, with a 1.6- (relative frequency) to 2.5-fold (count) increase in African-derived tumours. Furthermore, we found duplication events to be associated with CDK12 inactivation and MYC copy number gain, and deletion events associated with SPOP mutation. Overall, African-derived tumours were 2-fold more likely to present with a hyper-SV subtype. In addition to hyper-duplication and deletion subtypes, we describe a new hyper-translocation subtype. While we confirm a lower TMPRSS2-ERG fusion-positive rate in tumours from African cases (10% versus 33%), novel African-specific PCa ETS family member and TMPRSS2 fusion partners were identified, including LINC01525, FBXO7, GTF3C2, NTNG1 and YPEL5. Notably, we found 74 somatic SV hotspots impacting 18 new candidate driver genes, with CADM2, LSAMP, PTPRD, PDE4D and PACRG having therapeutic implications for African patients.
Conclusions: In this first African-inclusive SV study for high-risk PCa, we demonstrate the power of SV interrogation for the identification of novel subtypes, oncogenic drivers and therapeutic targets. Identifying a novel spectrum of SVs in tumours derived from African patients provides a mechanism that may contribute, at least in part, to the observed ethnic disparity in advanced PCa presentation in men of African ancestry.
(© 2022. The Author(s).)
Databáze: MEDLINE
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