Genome-wide interrogation of structural variation reveals novel African-specific prostate cancer oncogenic drivers
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,...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-08-01
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| Series: | Genome Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13073-022-01096-w |
| _version_ | 1798004454352486400 |
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| author | Tingting Gong Weerachai Jaratlerdsiri Jue Jiang Cali Willet Tracy Chew Sean M. Patrick Ruth J. Lyons Anne-Maree Haynes Gabriela Pasqualim Ilma Simoni Brum Phillip D. Stricker Shingai B. A. Mutambirwa Rosemarie Sadsad Anthony T. Papenfuss Riana M. S. Bornman Eva K. F. Chan Vanessa M. Hayes |
| author_facet | Tingting Gong Weerachai Jaratlerdsiri Jue Jiang Cali Willet Tracy Chew Sean M. Patrick Ruth J. Lyons Anne-Maree Haynes Gabriela Pasqualim Ilma Simoni Brum Phillip D. Stricker Shingai B. A. Mutambirwa Rosemarie Sadsad Anthony T. Papenfuss Riana M. S. Bornman Eva K. F. Chan Vanessa M. Hayes |
| author_sort | Tingting Gong |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-11T12:24:04Z |
| format | Article |
| id | doaj.art-be0eca2467ac4ce4ac4446a41eb7f6fd |
| institution | Directory Open Access Journal |
| issn | 1756-994X |
| language | English |
| last_indexed | 2024-04-11T12:24:04Z |
| publishDate | 2022-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Genome Medicine |
| spelling | doaj.art-be0eca2467ac4ce4ac4446a41eb7f6fd2022-12-22T04:24:01ZengBMCGenome Medicine1756-994X2022-08-0114111410.1186/s13073-022-01096-wGenome-wide interrogation of structural variation reveals novel African-specific prostate cancer oncogenic driversTingting Gong0Weerachai Jaratlerdsiri1Jue Jiang2Cali Willet3Tracy Chew4Sean M. Patrick5Ruth J. Lyons6Anne-Maree Haynes7Gabriela Pasqualim8Ilma Simoni Brum9Phillip D. Stricker10Shingai B. A. Mutambirwa11Rosemarie Sadsad12Anthony T. Papenfuss13Riana M. S. Bornman14Eva K. F. Chan15Vanessa M. Hayes16Ancestry and Health Genomics Laboratory, Charles Perkins Centre, School of Medical Sciences, Faculty of Medicine and Health, University of SydneyAncestry and Health Genomics Laboratory, Charles Perkins Centre, School of Medical Sciences, Faculty of Medicine and Health, University of SydneyAncestry and Health Genomics Laboratory, Charles Perkins Centre, School of Medical Sciences, Faculty of Medicine and Health, University of SydneySydney Informatics Hub, University of SydneySydney Informatics Hub, University of SydneySchool of Health Systems and Public Health, University of PretoriaGenomics and Epigenetics Theme, Garvan Institute of Medical ResearchGenomics and Epigenetics Theme, Garvan Institute of Medical ResearchEndocrine and Tumor Molecular Biology Laboratory, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do SulEndocrine and Tumor Molecular Biology Laboratory, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do SulGenomics and Epigenetics Theme, Garvan Institute of Medical ResearchDepartment of Urology, Sefako Makgatho Health Science University, Dr George Mukhari Academic Hospital, MedunsaSydney Informatics Hub, University of SydneyBioinformatics Division, The Walter and Eliza Hall Institute of Medical ResearchSchool of Health Systems and Public Health, University of PretoriaGenomics and Epigenetics Theme, Garvan Institute of Medical ResearchAncestry and Health Genomics Laboratory, Charles Perkins Centre, School of Medical Sciences, Faculty of Medicine and Health, University of SydneyAbstract 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.https://doi.org/10.1186/s13073-022-01096-wChromosomal instabilityProstate cancerAfrican ancestryAdvanced diseaseEthnic disparityWhole genome sequencing |
| spellingShingle | Tingting Gong Weerachai Jaratlerdsiri Jue Jiang Cali Willet Tracy Chew Sean M. Patrick Ruth J. Lyons Anne-Maree Haynes Gabriela Pasqualim Ilma Simoni Brum Phillip D. Stricker Shingai B. A. Mutambirwa Rosemarie Sadsad Anthony T. Papenfuss Riana M. S. Bornman Eva K. F. Chan Vanessa M. Hayes Genome-wide interrogation of structural variation reveals novel African-specific prostate cancer oncogenic drivers Genome Medicine Chromosomal instability Prostate cancer African ancestry Advanced disease Ethnic disparity Whole genome sequencing |
| title | Genome-wide interrogation of structural variation reveals novel African-specific prostate cancer oncogenic drivers |
| title_full | Genome-wide interrogation of structural variation reveals novel African-specific prostate cancer oncogenic drivers |
| title_fullStr | Genome-wide interrogation of structural variation reveals novel African-specific prostate cancer oncogenic drivers |
| title_full_unstemmed | Genome-wide interrogation of structural variation reveals novel African-specific prostate cancer oncogenic drivers |
| title_short | Genome-wide interrogation of structural variation reveals novel African-specific prostate cancer oncogenic drivers |
| title_sort | genome wide interrogation of structural variation reveals novel african specific prostate cancer oncogenic drivers |
| topic | Chromosomal instability Prostate cancer African ancestry Advanced disease Ethnic disparity Whole genome sequencing |
| url | https://doi.org/10.1186/s13073-022-01096-w |
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