TY - JOUR
T1 - African-specific molecular taxonomy of prostate cancer
AU - Jaratlerdsiri, Weerachai
AU - Jiang, Jue
AU - Gong, Tingting
AU - Patrick, Sean M.
AU - Willet, Cali
AU - Chew, Tracy
AU - Lyons, Ruth J.
AU - Haynes, Anne Maree
AU - Pasqualim, Gabriela
AU - Louw, Melanie
AU - Kench, James G.
AU - Campbell, Raymond
AU - Horvath, Lisa G.
AU - Chan, Eva K.F.
AU - Wedge, David C.
AU - Sadsad, Rosemarie
AU - Brum, Ilma Simoni
AU - Mutambirwa, Shingai B.A.
AU - Stricker, Phillip D.
AU - Bornman, M. S.Riana
AU - Hayes, Vanessa M.
N1 - Funding Information:
The work presented was supported by the National Health and Medical Research Council (NHMRC) of Australia through a Project Grant (APP1165762, to V.M.H.), NHMRC Ideas Grants (APP2001098, to V.M.H. and M.S.R.B.; APP2010551, to V.M.H.), University of Sydney Bridging Grant (G199756, to V.M.H.), and through the US Department of Defense (DoD) Prostate Cancer Research Program (PCRP) Idea Development Award TARGET Africa (PC200390, to W.J., S.M.P., D.C.W., S.B.A.M., M.S.R.B. and V.M.H.). We acknowledge the use of the National Computational Infrastructure (NCI), which is supported by the Australian Government, and accessed through the National Computational Merit Allocation Scheme (V.M.H., E.K.F.C. and W.J.), the Intersect Computational Merit Allocation Scheme (V.M.H.), Intersect Australia Limited and the Sydney Informatics Hub, Core Research Facility, and we acknowledge the staff at the Garvan Institute of Medical Research’s Kinghorn Centre for Clinical Genomics (KCCG) core facility for genome sequencing. Recruitment, sampling and processing for the Southern African Prostate Cancer Study (SAPCS), as required for the purpose of this study, was supported by the Cancer Association of South Africa (CANSA; M.S.R.B. and V.M.H.). V.M.H. is supported by the Petre Foundation through the University of Sydney Foundation; A.-M.H. and W.J. by a Cancer Institute of New South Wales (CINSW) Program Grant (TPG172146 to L.G.H., J.G.K., P.D.S. and V.M.H.), with additional support to W.J. provided by the Prostate Cancer Research Alliance Australian Government and Movember Foundation Collaboration PRECEPT (prostate cancer prognosis and treatment study, led by N. Corcoran). We thank the patients and their families who contributed to this study; without their contribution, this research would not be possible; the many clinical staff across the SAPCS (South Africa), the St Vincent’s Hospital Sydney (Australia) and Endocrine and Tumor Molecular Biology Laboratory (Brazil) for their contributions, who over many years have recruited patients and provided samples to these critical bioresources, with special recognition of P. Venter, R. L. Monare and S. van Zyl for their contributions as inaugural members of the SAPCS.
Funding Information:
The work presented was supported by the National Health and Medical Research Council (NHMRC) of Australia through a Project Grant (APP1165762, to V.M.H.), NHMRC Ideas Grants (APP2001098, to V.M.H. and M.S.R.B.; APP2010551, to V.M.H.), University of Sydney Bridging Grant (G199756, to V.M.H.), and through the US Department of Defense (DoD) Prostate Cancer Research Program (PCRP) Idea Development Award TARGET Africa (PC200390, to W.J., S.M.P., D.C.W., S.B.A.M., M.S.R.B. and V.M.H.). We acknowledge the use of the National Computational Infrastructure (NCI), which is supported by the Australian Government, and accessed through the National Computational Merit Allocation Scheme (V.M.H., E.K.F.C. and W.J.), the Intersect Computational Merit Allocation Scheme (V.M.H.), Intersect Australia Limited and the Sydney Informatics Hub, Core Research Facility, and we acknowledge the staff at the Garvan Institute of Medical Research’s Kinghorn Centre for Clinical Genomics (KCCG) core facility for genome sequencing. Recruitment, sampling and processing for the Southern African Prostate Cancer Study (SAPCS), as required for the purpose of this study, was supported by the Cancer Association of South Africa (CANSA; M.S.R.B. and V.M.H.). V.M.H. is supported by the Petre Foundation through the University of Sydney Foundation; A.-M.H. and W.J. by a Cancer Institute of New South Wales (CINSW) Program Grant (TPG172146 to L.G.H., J.G.K., P.D.S. and V.M.H.), with additional support to W.J. provided by the Prostate Cancer Research Alliance Australian Government and Movember Foundation Collaboration PRECEPT (prostate cancer prognosis and treatment study, led by N. Corcoran). We thank the patients and their families who contributed to this study; without their contribution, this research would not be possible; the many clinical staff across the SAPCS (South Africa), the St Vincent’s Hospital Sydney (Australia) and Endocrine and Tumor Molecular Biology Laboratory (Brazil) for their contributions, who over many years have recruited patients and provided samples to these critical bioresources, with special recognition of P. Venter, R. L. Monare and S. van Zyl for their contributions as inaugural members of the SAPCS.
Publisher Copyright:
© 2022, Crown.
PY - 2022/9/15
Y1 - 2022/9/15
N2 - Prostate cancer is characterized by considerable geo-ethnic disparity. African ancestry is a significant risk factor, with mortality rates across sub-Saharan Africa of 2.7-fold higher than global averages1. The contributing genetic and non-genetic factors, and associated mutational processes, are unknown2,3. Here, through whole-genome sequencing of treatment-naive prostate cancer samples from 183 ancestrally (African versus European) and globally distinct patients, we generate a large cancer genomics resource for sub-Saharan Africa, identifying around 2 million somatic variants. Significant African-ancestry-specific findings include an elevated tumour mutational burden, increased percentage of genome alteration, a greater number of predicted damaging mutations and a higher total of mutational signatures, and the driver genes NCOA2, STK19, DDX11L1, PCAT1 and SETBP1. Examining all somatic mutational types, we describe a molecular taxonomy for prostate cancer differentiated by ancestry and defined as global mutational subtypes (GMS). By further including Chinese Asian data, we confirm that GMS-B (copy-number gain) and GMS-D (mutationally noisy) are specific to African populations, GMS-A (mutationally quiet) is universal (all ethnicities) and the African–European-restricted subtype GMS-C (copy-number losses) predicts poor clinical outcomes. In addition to the clinical benefit of including individuals of African ancestry, our GMS subtypes reveal different evolutionary trajectories and mutational processes suggesting that both common genetic and environmental factors contribute to the disparity between ethnicities. Analogous to gene–environment interaction—defined here as a different effect of an environmental surrounding in people with different ancestries or vice versa—we anticipate that GMS subtypes act as a proxy for intrinsic and extrinsic mutational processes in cancers, promoting global inclusion in landmark studies.
AB - Prostate cancer is characterized by considerable geo-ethnic disparity. African ancestry is a significant risk factor, with mortality rates across sub-Saharan Africa of 2.7-fold higher than global averages1. The contributing genetic and non-genetic factors, and associated mutational processes, are unknown2,3. Here, through whole-genome sequencing of treatment-naive prostate cancer samples from 183 ancestrally (African versus European) and globally distinct patients, we generate a large cancer genomics resource for sub-Saharan Africa, identifying around 2 million somatic variants. Significant African-ancestry-specific findings include an elevated tumour mutational burden, increased percentage of genome alteration, a greater number of predicted damaging mutations and a higher total of mutational signatures, and the driver genes NCOA2, STK19, DDX11L1, PCAT1 and SETBP1. Examining all somatic mutational types, we describe a molecular taxonomy for prostate cancer differentiated by ancestry and defined as global mutational subtypes (GMS). By further including Chinese Asian data, we confirm that GMS-B (copy-number gain) and GMS-D (mutationally noisy) are specific to African populations, GMS-A (mutationally quiet) is universal (all ethnicities) and the African–European-restricted subtype GMS-C (copy-number losses) predicts poor clinical outcomes. In addition to the clinical benefit of including individuals of African ancestry, our GMS subtypes reveal different evolutionary trajectories and mutational processes suggesting that both common genetic and environmental factors contribute to the disparity between ethnicities. Analogous to gene–environment interaction—defined here as a different effect of an environmental surrounding in people with different ancestries or vice versa—we anticipate that GMS subtypes act as a proxy for intrinsic and extrinsic mutational processes in cancers, promoting global inclusion in landmark studies.
UR - http://www.scopus.com/inward/record.url?scp=85137208223&partnerID=8YFLogxK
U2 - 10.1038/s41586-022-05154-6
DO - 10.1038/s41586-022-05154-6
M3 - Article
C2 - 36045292
AN - SCOPUS:85137208223
SN - 0028-0836
VL - 609
SP - 552
EP - 559
JO - Nature
JF - Nature
IS - 7927
ER -