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1. Prostate cancer risk stratification improvement across multiple ancestries with new polygenic hazard score

Author

Huynh-Le, Minh-Phuong, Karunamuni, Roshan, Fan, Chun Chieh, Asona, Lui, Thompson, Wesley K, Martinez, Maria Elena, Eeles, Rosalind A, Kote-Jarai, Zsofia, Muir, Kenneth R, Lophatananon, Artitaya, Schleutker, Johanna, Pashayan, Nora, Batra, Jyotsna, Grönberg, Henrik, Neal, David E, Nordestgaard, Børge G, Tangen, Catherine M, MacInnis, Robert J, Wolk, Alicja, Albanes, Demetrius, Haiman, Christopher A, Travis, Ruth C, Blot, William J, Stanford, Janet L, Mucci, Lorelei A, West, Catharine ML, Nielsen, Sune F, Kibel, Adam S, Cussenot, Olivier, Berndt, Sonja I, Koutros, Stella, Sørensen, Karina Dalsgaard, Cybulski, Cezary, Grindedal, Eli Marie, Menegaux, Florence, Park, Jong Y, Ingles, Sue A, Maier, Christiane, Hamilton, Robert J, Rosenstein, Barry S, Lu, Yong-Jie, Watya, Stephen, Vega, Ana, Kogevinas, Manolis, Wiklund, Fredrik, Penney, Kathryn L, Huff, Chad D, Teixeira, Manuel R, Multigner, Luc, Leach, Robin J, Brenner, Hermann, John, Esther M, Kaneva, Radka, Logothetis, Christopher J, Neuhausen, Susan L, De Ruyck, Kim, Ost, Piet, Razack, Azad, Newcomb, Lisa F, Fowke, Jay H, Gamulin, Marija, Abraham, Aswin, Claessens, Frank, Castelao, Jose Esteban, Townsend, Paul A, Crawford, Dana C, Petrovics, Gyorgy, Van Schaik, Ron HN, Parent, Marie-Élise, Hu, Jennifer J, Zheng, Wei, UKGPCS Collaborators, APCB (Australian Prostate Cancer BioResource), NC-LA PCaP Investigators, IMPACT Study Steering Committee And Collaborators, Canary PASS Investigators, Profile Study Steering Committee, PRACTICAL Consortium, Mills, Ian G, Andreassen, Ole A, Dale, Anders M, Seibert, Tyler M, Huynh-Le, Minh-Phuong [0000-0002-5025-4709], Fan, Chun Chieh [0000-0001-9437-2128], Asona, Lui [0000-0002-0076-3492], Eeles, Rosalind A [0000-0002-3698-6241], Muir, Kenneth R [0000-0001-6429-988X], Schleutker, Johanna [0000-0002-1863-0305], Pashayan, Nora [0000-0003-0843-2468], Batra, Jyotsna [0000-0003-4646-6247], Grönberg, Henrik [0000-0002-1073-2753], Nordestgaard, Børge G [0000-0002-1954-7220], Wolk, Alicja [0000-0001-7387-6845], Travis, Ruth C [0000-0002-9571-0763], West, Catharine ML [0000-0002-0839-3449], Sørensen, Karina Dalsgaard [0000-0002-4902-5490], Menegaux, Florence [0000-0003-3363-6411], Park, Jong Y [0000-0002-6384-6447], Lu, Yong-Jie [0000-0001-6174-6621], Vega, Ana [0000-0002-7416-5137], Kogevinas, Manolis [0000-0002-9605-0461], Wiklund, Fredrik [0000-0002-4623-0544], Teixeira, Manuel R [0000-0002-4896-5982], Multigner, Luc [0000-0003-3205-8568], Brenner, Hermann [0000-0002-6129-1572], Ost, Piet [0000-0002-2203-4848], Fowke, Jay H [0000-0003-3803-8162], Gamulin, Marija [0000-0003-2431-7910], Abraham, Aswin [0000-0003-0024-3339], Crawford, Dana C [0000-0002-6437-6248], Petrovics, Gyorgy [0000-0003-3732-284X], Parent, Marie-Élise [0000-0002-4196-3773], Zheng, Wei [0000-0003-1226-070X], Seibert, Tyler M [0000-0002-4089-7399], and Apollo - University of Cambridge Repository

Subjects
Male, Urologic Diseases, Aging, Oncology and Carcinogenesis, Polymorphism, Single Nucleotide, Risk Assessment, UKGPCS collaborators, Risk Factors, NC-LA PCaP Investigators, Genetics, PRACTICAL Consortium, Humans, Genetic Predisposition to Disease, Polymorphism, Early Detection of Cancer, Cancer, Canary PASS Investigators, IMPACT Study Steering Committee and Collaborators, Profile Study Steering Committee, Prevention, Prostate Cancer, APCB, Prostatic Neoplasms, Single Nucleotide, Prostate-Specific Antigen, Urology & Nephrology, Good Health and Well Being
Abstract

Funder: University of California (#C21CR2060), the Prostate Cancer Foundation, Funder: Research Council of Norway (#223273), KG Jebsen Stiftelsen, and South East Norway Health Authority, BACKGROUND: Prostate cancer risk stratification using single-nucleotide polymorphisms (SNPs) demonstrates considerable promise in men of European, Asian, and African genetic ancestries, but there is still need for increased accuracy. We evaluated whether including additional SNPs in a prostate cancer polygenic hazard score (PHS) would improve associations with clinically significant prostate cancer in multi-ancestry datasets. METHODS: In total, 299 SNPs previously associated with prostate cancer were evaluated for inclusion in a new PHS, using a LASSO-regularized Cox proportional hazards model in a training dataset of 72,181 men from the PRACTICAL Consortium. The PHS model was evaluated in four testing datasets: African ancestry, Asian ancestry, and two of European Ancestry-the Cohort of Swedish Men (COSM) and the ProtecT study. Hazard ratios (HRs) were estimated to compare men with high versus low PHS for association with clinically significant, with any, and with fatal prostate cancer. The impact of genetic risk stratification on the positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was also measured. RESULTS: The final model (PHS290) had 290 SNPs with non-zero coefficients. Comparing, for example, the highest and lowest quintiles of PHS290, the hazard ratios (HRs) for clinically significant prostate cancer were 13.73 [95% CI: 12.43-15.16] in ProtecT, 7.07 [6.58-7.60] in African ancestry, 10.31 [9.58-11.11] in Asian ancestry, and 11.18 [10.34-12.09] in COSM. Similar results were seen for association with any and fatal prostate cancer. Without PHS stratification, the PPV of PSA testing for clinically significant prostate cancer in ProtecT was 0.12 (0.11-0.14). For the top 20% and top 5% of PHS290, the PPV of PSA testing was 0.19 (0.15-0.22) and 0.26 (0.19-0.33), respectively. CONCLUSIONS: We demonstrate better genetic risk stratification for clinically significant prostate cancer than prior versions of PHS in multi-ancestry datasets. This is promising for implementing precision-medicine approaches to prostate cancer screening decisions in diverse populations.

Published
2022

2. Polygenic hazard score is associated with prostate cancer in multi-ethnic populations

Author

Florence Menegaux, William J. Blot, Henrik Grönberg, Luc Multigner, Sune F. Nielsen, Stella Koutros, Frank Claessens, Manuela Gago-Dominguez, Kathryn L. Penney, Tyler M. Seibert, Cezary Cybulski, Jennifer J. Hu, Hermann Brenner, Radka Kaneva, Sue A. Ingles, Catherine M. Tangen, Ian G. Mills, Janet L. Stanford, Karina Dalsgaard Sørensen, Ruth C. Travis, Marie-Élise Parent, Monique J. Roobol, Nora Pashayan, Jyotsna Batra, Maria Elena Martinez, Anders M. Dale, Wei Zheng, Kay-Tee Khaw, Chad D. Huff, Chun Chieh Fan, Paul A. Townsend, Kim De Ruyck, Yong-Jie Lu, Eli Marie Grindedal, Hardev Pandha, Sonja I. Berndt, Susan L. Neuhausen, Alicja Wolk, Apcb, Wesley K. Thompson, Maureen Sanderson, Demetrius Albanes, Stephen N. Thibodeau, Christiane Maier, Kenneth Muir, Robin J. Leach, Børge G. Nordestgaard, Ole A. Andreassen, Fredrik Wiklund, Graham G. Giles, Zsofia Kote-Jarai, Catharine M L West, Minh-Phuong Huynh-Le, Manolis Kogevinas, Manuel R. Teixeira, Jong Y. Park, Johanna Schleutker, Marija Gamulin, Freddie C. Hamdy, William S. Bush, Barry S. Rosenstein, Stephen Watya, Roshan Karunamuni, Richard M. Martin, Nc-La PCaP Investigators, Ana Vega, Adam S. Kibel, Lisa A. Cannon-Albright, Azad Hassan Abdul Razack, Esther M. John, Christopher J. Logothetis, Jay H. Fowke, Nawaid Usmani, David E. Neal, Canary Pass Investigators, Rosalind A. Eeles, Robert J. Hamilton, Lisa F. Newcomb, Jenny L Donovan, Olivier Cussenot, Lorelei A. Mucci, University of California [San Diego] (UC San Diego), University of California, The institute of cancer research [London], University of Manchester [Manchester], University of Turku, Centre for Cancer Genetic Epidemiology [Cambridge], Department of Oncology-University of Cambridge [UK] (CAM), University College of London [London] (UCL), Centre de Recherche pour les Pathologies Prostatiques [Paris] (CeRePP), Sorbonne Université (SU), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut de recherche en santé, environnement et travail (Irset), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), This study was funded in part by a grant from the United States National Institute of Health/National Institute of Biomedical Imaging and Bioengineering (#K08EB026503), United States Department of Defense (#W81XWH-13-1-0391), University of California CRCC C21CR2060, the Research Council of Norway (#223273), K.G. Jebsen Stiftelsen, and South East Norway Health Authority. RM Martin is supported in part by the National Institute for Health Research Bristol Biomedical Research Centre. The CAP trial is funded by Cancer Research UK and the UK Department of Health (C11043/A4286, C18281/A8145, C18281/A11326, C18281/A15064, and C18281/A24432). R.M. Martin was supported by a Cancer Research UK (C18281/A19169) program grant (the Integrative Cancer Epidemiology Programme). Funding for the PRACTICAL consortium member studies is detailed in the Supplementary Information., University of California (UC), University of Cambridge [UK] (CAM)-Department of Oncology, Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Huynh-Le, Minh-Phuong [0000-0002-5025-4709], Fan, Chun Chieh [0000-0001-9437-2128], Eeles, Rosalind A [0000-0002-3698-6241], Muir, Kenneth [0000-0001-6429-988X], Schleutker, Johanna [0000-0002-1863-0305], Pashayan, Nora [0000-0003-0843-2468], Batra, Jyotsna [0000-0003-4646-6247], Grönberg, Henrik [0000-0002-1073-2753], Martin, Richard M [0000-0002-7992-7719], Nordestgaard, Børge G [0000-0002-1954-7220], Wiklund, Fredrik [0000-0002-4623-0544], Giles, Graham G [0000-0003-4946-9099], Wolk, Alicja [0000-0001-7387-6845], Travis, Ruth C [0000-0002-9571-0763], Zheng, Wei [0000-0003-1226-070X], West, Catharine ML [0000-0002-0839-3449], Sørensen, Karina Dalsgaard [0000-0002-4902-5490], Park, Jong Y [0000-0002-6384-6447], Vega, Ana [0000-0002-7416-5137], Teixeira, Manuel R [0000-0002-4896-5982], Multigner, Luc [0000-0003-3205-8568], Cannon-Albright, Lisa [0000-0003-2602-3668], Gamulin, Marija [0000-0003-2431-7910], Bush, William S [0000-0002-9729-6519], Roobol, Monique J [0000-0001-6967-1708], Andreassen, Ole A [0000-0002-4461-3568], Seibert, Tyler M [0000-0002-4089-7399], Apollo - University of Cambridge Repository, and Clinical Chemistry

Subjects
0301 basic medicine, Oncology, Male, Multifactorial Inheritance, Aging, Multivariate analysis, Ethnic Groups/genetics, General Physics and Astronomy, UKGPCS collaborators, Prostate cancer, 0302 clinical medicine, Urologi och njurmedicin, Ethnicity, risk factors, PRACTICAL Consortium, genetics, Stage (cooking), AgedEthnic Groups / genetics, Cancer, Multidisciplinary, Manchester Cancer Research Centre, Prostatic Neoplasms/genetics, Prostate Cancer, Hazard ratio, APCB, Middle Aged, Hazard, Health equity, 3. Good health, Multidisciplinary Sciences, 030220 oncology & carcinogenesis, Science & Technology - Other Topics, polygenic hazard score (PHS1), prostate cancer, ICEP, Medical Genetics, Urologic Diseases, medicine.medical_specialty, hazard, precision medicine, Science, Prostatic Neoplasms / genetics, [SDV.CAN]Life Sciences [q-bio]/Cancer, Ethnic Groups, survival, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Medical research, SDG 3 - Good Health and Well-being, Internal medicine, NC-LA PCaP Investigators, Genetic model, medicine, Urology and Nephrology, Humans, Neoplasm Invasiveness, Multifactorial Inheritance/genetics, Medicinsk genetik, Aged, Canary PASS Investigators, Science & Technology, IMPACT Study Steering Committee and Collaborators, business.industry, Profile Study Steering Committee, ResearchInstitutes_Networks_Beacons/mcrc, Prostatic Neoplasms, General Chemistry, medicine.disease, Multifactorial Inheritance / genetics, 030104 developmental biology, Multivariate Analysis, Self Report, business, Biomarkers
Abstract

Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS1) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS2 (PHS1, adapted for OncoArray) in a multi-ethnic dataset of 80,491 men (49,916 cases, 30,575 controls). PHS2 is associated with age at diagnosis of any and aggressive (Gleason score ≥ 7, stage T3-T4, PSA ≥ 10 ng/mL, or nodal/distant metastasis) cancer and prostate-cancer-specific death. Associations with cancer are significant within European (n = 71,856), Asian (n = 2,382), and African (n = 6,253) genetic ancestries (p, A polygenic hazard score (PHS1) improves prostate cancer screening accuracy in European patients. Here, the authors test the performance of a version compatible with OncoArray genotypes (PHS2) in a multi-ethnic dataset and find that it risk-stratifies men for any, aggressive, and fatal prostate cancer.

Published
2021

3. Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction

Author

Paul A. Townsend, Edward J. Saunders, Hidewaki Nakagawa, Manuel R. Teixeira, Graham Casey, Demetrius Albanes, Christine Neslund-Dudas, Sara Lindström, William S. Bush, Maren Weischer, Lisa A. Cannon-Albright, Rick A. Kittles, Peggy Wan, Martin Eklund, Stephen N. Thibodeau, Burcu F. Darst, Fredrik Wiklund, Nicholas Mancuso, Jeri Kim, Jong Y. Park, Johanna Schleutker, Maureen Sanderson, Samantha E.T. Larkin, Radka Kaneva, Hongwei Zhang, Daniel J. Schaid, Luc Multigner, Marie-Élise Parent, Robert Szulkin, Fredrick R. Schumacher, Geraldine Cancel-Tassin, Jianfeng Xu, Gill Barnett, Melissa C. Southey, Yuan Chun Ding, Alexander Lubwama, Maria Elena Martinez, Manolis Kogevinas, Linda Steele, Laurent Brureau, Shiv Srivastava, Maya Ghoussaini, Alison M. Dunning, Adam B. Murphy, Kenneth Muir, Edward Giovannucci, Mitchell J. Machiela, James L. Mohler, Jack A. Taylor, Robert N. Hoover, Sandeep Singhal, Chavdar Slavov, Guido Jenster, Frank Claessens, Neil Fleshner, Sara Benlloch, Gert De Meerleer, Michael B. Cook, Zan Sun, Harry Ostrer, Pascal Blanchet, Lynne R. Wilkens, Ali Amin Al Olama, Sue A. Ingles, Markus Aly, Jay H. Fowke, Agnieszka Michael, Yves Akoli Koudou, Victoria L. Stevens, Kathryn L. Penney, Ana Vega, Xin Sheng, Ron H.N. van Schaik, Zsofia Kote-Jarai, Kim De Ruyck, Christopher A. Haiman, Atushi Takahashi, Florence Menegaux, Judith A. Clements, Stephen K. Van Den Eeden, Brian D. Carter, Wayne D. Tilley, Antonio Finelli, Jennifer J. Hu, Hermann Brenner, Thomas Van den Broeck, Shan Chao Zhao, Azad Hassan Abdul Razack, Edward D. Yeboah, Sonja I. Berndt, Barbara Nemesure, Mark N. Brook, David V. Conti, Katarina Cuk, Teuvo L.J. Tammela, Ali Sahimi, Stephen J. Chanock, Loic Le Marchand, Gemma Castaño-Vinyals, Sune F. Nielsen, Sara S. Strom, Ann W. Hsing, Roberta McKean-Cowdin, David J. Hunter, Ian M. Thompson, Børge G. Nordestgaard, Jyotsna Batra, Paula Paulo, Masashi Fujita, Jennifer Cullen, Susan M. Gapstur, Sarah L. Kerns, Lorelei A. Mucci, Neil G. Burnet, Xueying Mao, Hui Yi Lin, Rohit Varma, Marija Gamulin, Wei Zheng, Thomas A. Sellers, Adam S. Kibel, Robert J. Hamilton, Leire Moya, Ninghan Feng, Laura E. Beane Freeman, James E. Mensah, Catherine M. Tangen, Shannon K. McDonnell, Matthew Parliament, Davor Lessel, Gail P. Risbridger, Mina Torres, Janet L. Stanford, Bettina F. Drake, Soo-Hwang Teo, Robert J. MacInnis, Stig E. Bojesen, Jeannette T. Bensen, William J. Blot, Stella Koutros, Robin J. Leach, Graham G. Giles, Piet Ost, Artitaya Lophatananon, Laura Fachal, Tomislav Kuliš, Peter Kraft, Monique J. Roobol, Elaine A. Ostrander, Niclas Håkansson, Anselm Hennis, Yukihide Momozawa, Anssi Auvinen, Koichi Matsuda, Steven Joniau, Lisa G. Horvath, Javier Llorca, Claire Aukim-Hastie, Bernd Holleczek, Daniel W. Lin, Gerald L. Andriole, John D. Carpten, Eli Marie Grindedal, Rosalind A. Eeles, Elio Riboli, Constance Turman, Martin Andreas Røder, Yong-Jie Lu, Tobias Nordström, Kai Uwe Saum, Esther M. John, Melinda C. Aldrich, Peter Iversen, Henrik Grönberg, John S. Witte, Andreia Brandão, Eric A. Klein, Olivier Cussenot, Barry S. Rosenstein, Stephen Watya, Jan Lubinski, Douglas F. Easton, Dana C. Crawford, Gyorgy Petrovics, Thomas J. Schnoeller, Richard M. Martin, Stephanie J. Weinstein, Jose Esteban Castelao, Suzanne K. Chambers, Tokhir Dadaev, Karina Dalsgaard Sørensen, Antonio Gómez-Caamaño, Lisa F. Newcomb, Csilla Sipeky, Lovise Maehle, Brandi Weaver, Susan L. Neuhausen, Christiane Maier, Alicja Wolk, Vanio Mitev, Thérèse Truong, Manuel Luedeke, Jenny L Donovan, Mariana C. Stern, Catharine M L West, Manuela Gago-Dominguez, Elizabeth T. H. Fontham, William B. Isaacs, David E. Neal, Christopher J. Logothetis, Alisha Chou, Jasmine Lim, Benjamin A. Rybicki, Kay-Tee Khaw, Meir J. Stampfer, Chad D. Huff, Thomas J. Hoffmann, Michael Borre, Freddie C. Hamdy, Nawaid Usmani, Cezary Cybulski, Craig C. Teerlink, Milan S. Geybels, Nora Pashayan, Timothy J. Key, Phyllis J. Goodman, Hardev Pandha, Ruth C. Travis, Yudong Wu, Dominika Wokołorczyk, Lilit C. Moss, University of Southern California (USC), Keck School of Medicine [Los Angeles], CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pointe-à-Pitre/Abymes [Guadeloupe], The institute of cancer research [London], U01CA194393, National Institutes of Health, NA, Achievement Rewards for College Scientists Foundation, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Urology, Clinical Chemistry, Darst, Burcu F [0000-0002-6205-4632], Chou, Alisha [0000-0001-7521-6373], Schumacher, Fredrick R [0000-0002-3073-7463], Dadaev, Tokhir [0000-0002-8268-0438], Brook, Mark N [0000-0002-8969-2378], Hoffmann, Thomas J [0000-0001-6893-4449], Takahashi, Atushi [0000-0001-7099-8767], Matsuda, Koichi [0000-0001-7292-2686], Fujita, Masashi [0000-0002-1457-6233], Muir, Kenneth [0000-0001-6429-988X], Stevens, Victoria L [0000-0003-0259-4407], Schleutker, Johanna [0000-0002-1863-0305], Sipeky, Csilla [0000-0002-8853-4722], Auvinen, Anssi [0000-0003-1125-4818], Giles, Graham G [0000-0003-4946-9099], Martin, Richard M [0000-0002-7992-7719], Nordestgaard, Børge G [0000-0002-1954-7220], Bojesen, Stig E [0000-0002-4061-4133], Røder, Martin Andreas [0000-0002-0019-5333], Batra, Jyotsna [0000-0003-4646-6247], Tilley, Wayne [0000-0003-1893-2626], Risbridger, Gail P [0000-0003-3089-4028], Gronberg, Henrik [0000-0002-1073-2753], Eklund, Martin [0000-0001-5032-5266], Nordström, Tobias [0000-0003-4915-7546], Pashayan, Nora [0000-0003-0843-2468], Dunning, Alison M [0000-0001-6651-7166], Travis, Ruth C [0000-0002-9571-0763], Riboli, Elio [0000-0001-6795-6080], Park, Jong Y [0000-0002-6384-6447], Weinstein, Stephanie J [0000-0002-3834-1535], Kraft, Peter [0000-0002-4472-8103], Ostrander, Elaine A [0000-0001-6075-9738], Wolk, Alicja [0000-0001-7387-6845], Håkansson, Niclas [0000-0001-7673-5554], Machiela, Mitchell J [0000-0001-6538-9705], Sørensen, Karina Dalsgaard [0000-0002-4902-5490], Zheng, Wei [0000-0003-1226-070X], Mensah, James E [0000-0003-4133-1722], Lu, Yong-Jie [0000-0001-6174-6621], West, Catharine ML [0000-0002-0839-3449], Cancel-Tassin, Géraldine [0000-0002-9583-6382], Truong, Thérèse [0000-0002-2943-6786], Vega, Ana [0000-0002-7416-5137], Gómez-Caamaño, Antonio [0000-0002-9773-4590], Fachal, Laura [0000-0002-7256-9752], Kerns, Sarah L [0000-0002-6503-0011], Ostrer, Harry [0000-0002-2209-5376], Teixeira, Manuel R [0000-0002-4896-5982], Brandão, Andreia [0000-0003-0938-1543], Cannon-Albright, Lisa [0000-0003-2602-3668], Multigner, Luc [0000-0003-3205-8568], Klein, Eric A [0000-0002-1783-0698], Murphy, Adam B [0000-0001-9977-3473], Michael, Agnieszka [0000-0002-7262-6227], Ost, Piet [0000-0002-2203-4848], Xu, Jianfeng [0000-0002-1343-8752], Teo, Soo-Hwang [0000-0002-0444-590X], Lessel, Davor [0000-0003-4496-244X], Kulis, Tomislav [0000-0002-0895-5691], Joniau, Steven [0000-0003-3195-9890], Bush, William S [0000-0002-9729-6519], Crawford, Dana C [0000-0002-6437-6248], Roobol, Monique J [0000-0001-6967-1708], Jenster, Guido [0000-0002-8658-2552], Van Den Eeden, Stephen K [0000-0002-5599-8387], Easton, Douglas F [0000-0003-2444-3247], Chanock, Stephen J [0000-0002-2324-3393], Wiklund, Fredrik [0000-0002-4623-0544], Eeles, Rosalind A [0000-0002-3698-6241], Haiman, Christopher A [0000-0002-0097-9971], and Apollo - University of Cambridge Repository

Subjects
Male, 8Q24, Genome-wide association study, Continental Population Groups/genetics, VARIANTS, Prostate cancer, 0302 clinical medicine, Risk Factors, Epidemiology, IMPUTATION, Odds Ratio, Prostatic Neoplasms/diagnosis, 0303 health sciences, education.field_of_study, Continental Population Groups, Manchester Cancer Research Centre, Middle Aged, Càncer--Aspectes genètics, 3. Good health, ODDS RATIOS, 06 Biological Sciences, 11 Medical and Health Sciences, medicine.medical_specialty, Population, Biology, prostate cancer, meta-analysis, SEQUENCE, Article, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Genetics, medicine, BREAST-CANCER, Humans, Genetic Predisposition to Disease, Neoplasm Invasiveness, education, 030304 developmental biology, Genetic association, [SDV.GEN]Life Sciences [q-bio]/Genetics, MUTATIONS, ResearchInstitutes_Networks_Beacons/mcrc, Racial Groups, Prostatic Neoplasms, Molecular Sequence Annotation, Odds ratio, medicine.disease, BRCA2, Pròstata--Càncer, Genetic Loci, 030217 neurology & neurosurgery, Imputation (genetics), Genètica, Demography, Developmental Biology, Genome-Wide Association Study
Abstract

International audience; Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.

Published
2021

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