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dc.contributor.author | Gong, Tingting![]() |
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dc.contributor.author | Jaratlerdsiri, Weerachai![]() |
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dc.contributor.author | Jiang, Jue![]() |
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dc.contributor.author | Willet, Cali![]() |
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dc.contributor.author | Chew, Tracy![]() |
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dc.contributor.author | Patrick, Sean Mark![]() |
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dc.contributor.author | Lyons, Ruth J.![]() |
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dc.contributor.author | Haynes, Anne‑Maree![]() |
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dc.contributor.author | Pasqualim, Gabriela![]() |
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dc.contributor.author | Brum, Ilma Simoni![]() |
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dc.contributor.author | Stricker, Phillip D.![]() |
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dc.contributor.author | Mutambirwa, Shingai B.A.![]() |
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dc.contributor.author | Sadsad, Rosemarie![]() |
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dc.contributor.author | Papenfuss, Anthony T.![]() |
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dc.contributor.author | Bornman, Maria S. (Riana)![]() |
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dc.contributor.author | Chan, Eva K.F.![]() |
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dc.contributor.author | Hayes, Vanessa M.![]() |
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dc.date.accessioned | 2023-07-19T11:39:32Z | |
dc.date.available | 2023-07-19T11:39:32Z | |
dc.date.issued | 2022-08-31 | |
dc.description | ADDITIONAL FILE 1: FIGURE S1. Concordant SV call generation from Manta and GRIDSS. FIGURE S2. Summary of SVs in each type, compared to other studies. FIGURE S3. CIRCOS plot of hyper-SV mutated tumours. FIGURE S4. The spread of SV breakpoints and samples in each 1 Mbp genomic bin. FIGURE S5. TMPRSS2-ERG fusion with interstitial region retention. TABLE S1. Clinical and pathological characteristics of 180 prostate cancer patients included in this study. TABLE S2. Biallelic assessment of CDK12 in hyper-duplicated samples. TABLE S3. Biallelic assessment of BRCA2 in hyper-deleted samples. | en_US |
dc.description | ADDITIONAL FILE 2: TABLE S4. Summary of gene fusions identified from SVs. ADDITIONAL FILE 3: TABLE S5. SV calls resulting in gene fusions. | en_US |
dc.description | DATA AND MATERIALS AVAILABILITY : The datasets analysed in this study were obtained and accessible through Jaratlerdsiri et al [6], with sequence data deposited in the European GenomePhenome Archive (EGA; https://ega-archive.org) under overarching accession EGAS00001006425 and including the Southern African Prostate Cancer Study (SAPCS) Dataset (EGAD00001009067) and Garvan/St Vincent’s Prostate Cancer Database (EGAD00001009066). The computational code used to analyse SV subtypes, SV hotspots and gene fusions is available on GitHub [68]. | en_US |
dc.description.abstract | 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. | en_US |
dc.description.department | School of Health Systems and Public Health (SHSPH) | en_US |
dc.description.librarian | am2023 | en_US |
dc.description.sponsorship | The Medical Health and Medical Research Council (NHMRC) of Australia, University of Sydney Bridging Grant, the USA. Department of Defense (DoD) Prostate Cancer Research Program (PCRP) Idea Development. | en_US |
dc.description.uri | https://genomemedicine.biomedcentral.com | en_US |
dc.identifier.citation | Gong, T., Jaratlerdsiri, W., Jiang, J. et al. 2022, 'Genome‑wide interrogation of structural variation reveals novel African‑specific prostate cancer oncogenic drivers', Genome Medicine, vol. 14, no. 1, art. 100, pp. 1-14, doi : 10.1186/s13073-022-01096-w. | en_US |
dc.identifier.issn | 1756-994X | |
dc.identifier.other | 10.1186/s13073-022-01096-w | |
dc.identifier.uri | http://hdl.handle.net/2263/91549 | |
dc.language.iso | en | en_US |
dc.publisher | BMC | en_US |
dc.rights | © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License. | en_US |
dc.subject | Chromosomal instability | en_US |
dc.subject | Prostate cancer | en_US |
dc.subject | African ancestry | en_US |
dc.subject | Advanced disease | en_US |
dc.subject | Ethnic disparity | en_US |
dc.subject | Whole genome sequencing | en_US |
dc.subject | SDG-03: Good health and well-being | en_US |
dc.title | Genome-wide interrogation of structural variation reveals novel African-specific prostate cancer oncogenic drivers | en_US |
dc.type | Article | en_US |