Burcu F Darst1, Tokhir Dadaev2, Ed Saunders2, Xin Sheng1, Peggy Wan1, Loreall Pooler1, Lucy Y Xia1, Stephen Chanock3, Sonja I Berndt3, Susan M Gapstur4, Victoria Stevens4, Demetrius Albanes3, Stephanie J Weinstein3, Vincent Gnanapragasam5, Graham G Giles6,7,8, Tu Nguyen-Dumont7,9, Roger L Milne6,7,8, Mark Pomerantz10, Julie A Schmidt11, Lorelei Mucci12, William J Catalona13, Kurt N Hetrick14, Kimberly F Doheny14, Robert J MacInnis6,8, Melissa C Southey6,7,9, Rosalind A Eeles2,15, Fredrik Wiklund16, Zsofia Kote-Jarai2, David V Conti1, Christopher A Haiman1. 1. Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. 2. The Institute of Cancer Research, London, UK. 3. National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. 4. American Cancer Society, Atlanta, GA, USA. 5. Department of Surgery and Oncology, Academic Urology Group, University of Cambridge, Cambridge, UK. 6. Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia. 7. Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Melbourne, Victoria, Australia. 8. Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Victoria, Australia. 9. Department of Clinical Pathology, The University of Melbourne, Victoria, Australia. 10. Dana Farber Cancer Institute, Boston, MA, USA. 11. University of Oxford, Oxford, UK. 12. Harvard University, Cambridge, MA, USA. 13. Northwestern University Feinberg School of Medicine, Chicago, IL, USA. 14. Department of Genetic Medicine, Center for Inherited Disease Research, Johns Hopkins School of Medicine, Baltimore, MD, USA. 15. The Royal Marsden NHS Foundation Trust, London, UK. 16. Karolinska Institute, Solna, Sweden.
Abstract
BACKGROUND: There is an urgent need to identify factors specifically associated with aggressive prostate cancer (PCa) risk. We investigated whether rare pathogenic, likely pathogenic, or deleterious (P/LP/D) germline variants in DNA repair genes are associated with aggressive PCa risk in a case-case study of aggressive vs nonaggressive disease. METHODS: Participants were 5545 European-ancestry men, including 2775 nonaggressive and 2770 aggressive PCa cases, which included 467 metastatic cases (16.9%). Samples were assembled from 12 international studies and germline sequenced together. Rare (minor allele frequency < 0.01) P/LP/D variants were analyzed for 155 DNA repair genes. We compared single variant, gene-based, and DNA repair pathway-based burdens by disease aggressiveness. All statistical tests are 2-sided. RESULTS: BRCA2 and PALB2 had the most statistically significant gene-based associations, with 2.5% of aggressive and 0.8% of nonaggressive cases carrying P/LP/D BRCA2 alleles (odds ratio [OR] = 3.19, 95% confidence interval [CI] = 1.94 to 5.25, P = 8.58 × 10-7) and 0.65% of aggressive and 0.11% of nonaggressive cases carrying P/LP/D PALB2 alleles (OR = 6.31, 95% CI = 1.83 to 21.68, P = 4.79 × 10-4). ATM had a nominal association, with 1.6% of aggressive and 0.8% of nonaggressive cases carrying P/LP/D ATM alleles (OR = 1.88, 95% CI = 1.10 to 3.22, P = .02). In aggregate, P/LP/D alleles within 24 literature-curated candidate PCa DNA repair genes were more common in aggressive than nonaggressive cases (carrier frequencies = 14.2% vs 10.6%, respectively; P = 5.56 × 10-5). However, this difference was non-statistically significant (P = .18) on excluding BRCA2, PALB2, and ATM. Among these 24 genes, P/LP/D carriers had a 1.06-year younger diagnosis age (95% CI = -1.65 to 0.48, P = 3.71 × 10-4). CONCLUSIONS: Risk conveyed by DNA repair genes is largely driven by rare P/LP/D alleles within BRCA2, PALB2, and ATM. These findings support the importance of these genes in both screening and disease management considerations.
BACKGROUND: There is an urgent need to identify factors specifically associated with aggressive prostate cancer (PCa) risk. We investigated whether rare pathogenic, likely pathogenic, or deleterious (P/LP/D) germline variants in DNA repair genes are associated with aggressive PCa risk in a case-case study of aggressive vs nonaggressive disease. METHODS: Participants were 5545 European-ancestry men, including 2775 nonaggressive and 2770 aggressive PCa cases, which included 467 metastatic cases (16.9%). Samples were assembled from 12 international studies and germline sequenced together. Rare (minor allele frequency < 0.01) P/LP/D variants were analyzed for 155 DNA repair genes. We compared single variant, gene-based, and DNA repair pathway-based burdens by disease aggressiveness. All statistical tests are 2-sided. RESULTS: BRCA2 and PALB2 had the most statistically significant gene-based associations, with 2.5% of aggressive and 0.8% of nonaggressive cases carrying P/LP/D BRCA2 alleles (odds ratio [OR] = 3.19, 95% confidence interval [CI] = 1.94 to 5.25, P = 8.58 × 10-7) and 0.65% of aggressive and 0.11% of nonaggressive cases carrying P/LP/D PALB2 alleles (OR = 6.31, 95% CI = 1.83 to 21.68, P = 4.79 × 10-4). ATM had a nominal association, with 1.6% of aggressive and 0.8% of nonaggressive cases carrying P/LP/D ATM alleles (OR = 1.88, 95% CI = 1.10 to 3.22, P = .02). In aggregate, P/LP/D alleles within 24 literature-curated candidate PCa DNA repair genes were more common in aggressive than nonaggressive cases (carrier frequencies = 14.2% vs 10.6%, respectively; P = 5.56 × 10-5). However, this difference was non-statistically significant (P = .18) on excluding BRCA2, PALB2, and ATM. Among these 24 genes, P/LP/D carriers had a 1.06-year younger diagnosis age (95% CI = -1.65 to 0.48, P = 3.71 × 10-4). CONCLUSIONS: Risk conveyed by DNA repair genes is largely driven by rare P/LP/D alleles within BRCA2, PALB2, and ATM. These findings support the importance of these genes in both screening and disease management considerations.
Authors: T Ikonen; M P Matikainen; K Syrjäkoski; N Mononen; P A Koivisto; A Rökman; E H Seppälä; O-P Kallioniemi; T L J Tammela; J Schleutker Journal: J Med Genet Date: 2003-08 Impact factor: 6.318
Authors: Rong Na; S Lilly Zheng; Misop Han; Hongjie Yu; Deke Jiang; Sameep Shah; Charles M Ewing; Liti Zhang; Kristian Novakovic; Jacqueline Petkewicz; Kamalakar Gulukota; Donald L Helseth; Margo Quinn; Elizabeth Humphries; Kathleen E Wiley; Sarah D Isaacs; Yishuo Wu; Xu Liu; Ning Zhang; Chi-Hsiung Wang; Janardan Khandekar; Peter J Hulick; Daniel H Shevrin; Kathleen A Cooney; Zhoujun Shen; Alan W Partin; H Ballentine Carter; Michael A Carducci; Mario A Eisenberger; Sam R Denmeade; Michael McGuire; Patrick C Walsh; Brian T Helfand; Charles B Brendler; Qiang Ding; Jianfeng Xu; William B Isaacs Journal: Eur Urol Date: 2016-12-15 Impact factor: 20.096
Authors: L Joseph Su; Lenore Arab; Susan E Steck; Elizabeth T H Fontham; Jane C Schroeder; Jeannette T Bensen; James L Mohler Journal: Cancer Epidemiol Biomarkers Prev Date: 2011-04-05 Impact factor: 4.254
Authors: S M Edwards; D G R Evans; Q Hope; A R Norman; Y Barbachano; S Bullock; Z Kote-Jarai; J Meitz; A Falconer; P Osin; C Fisher; M Guy; S G Jhavar; A L Hall; L T O'Brien; B N Gehr-Swain; R A Wilkinson; M S Forrest; D P Dearnaley; A T Ardern-Jones; E C Page; D F Easton; R A Eeles Journal: Br J Cancer Date: 2010-08-24 Impact factor: 7.640
Authors: Piper Nicolosi; Elisa Ledet; Shan Yang; Scott Michalski; Brandy Freschi; Erin O'Leary; Edward D Esplin; Robert L Nussbaum; Oliver Sartor Journal: JAMA Oncol Date: 2019-04-01 Impact factor: 31.777
Authors: Daniel A Leongamornlert; Edward J Saunders; Sarah Wakerell; Ian Whitmore; Tokhir Dadaev; Clara Cieza-Borrella; Sarah Benafif; Mark N Brook; Jenny L Donovan; Freddie C Hamdy; David E Neal; Kenneth Muir; Koveela Govindasami; David V Conti; Zsofia Kote-Jarai; Rosalind A Eeles Journal: Eur Urol Date: 2019-02-15 Impact factor: 20.096
Authors: Elena Castro; Chee Goh; David Olmos; Ed Saunders; Daniel Leongamornlert; Malgorzata Tymrakiewicz; Nadiya Mahmud; Tokhir Dadaev; Koveela Govindasami; Michelle Guy; Emma Sawyer; Rosemary Wilkinson; Audrey Ardern-Jones; Steve Ellis; Debra Frost; Susan Peock; D Gareth Evans; Marc Tischkowitz; Trevor Cole; Rosemarie Davidson; Diana Eccles; Carole Brewer; Fiona Douglas; Mary E Porteous; Alan Donaldson; Huw Dorkins; Louise Izatt; Jackie Cook; Shirley Hodgson; M John Kennedy; Lucy E Side; Jacqueline Eason; Alex Murray; Antonis C Antoniou; Douglas F Easton; Zsofia Kote-Jarai; Rosalind Eeles Journal: J Clin Oncol Date: 2013-04-08 Impact factor: 44.544
Authors: Jian Sang; Tongwu Zhang; Jung Kim; Mengying Li; Angela C Pesatori; Dario Consonni; Lei Song; Jia Liu; Wei Zhao; Phuc H Hoang; Dave S Campbell; James Feng; Monica E D'Arcy; Naoise Synnott; Yingxi Chen; Zeni Wu; Bin Zhu; Xiaohong R Yang; Kevin M Brown; Jiyeon Choi; Jianxin Shi; Maria Teresa Landi Journal: Hum Mol Genet Date: 2022-10-10 Impact factor: 5.121
Authors: Dominika Wokołorczyk; Wojciech Kluźniak; Klaudia Stempa; Bogna Rusak; Tomasz Huzarski; Jacek Gronwald; Katarzyna Gliniewicz; Aniruddh Kashyap; Sylwia Morawska; Tadeusz Dębniak; Anna Jakubowska; Marek Szwiec; Paweł Domagała; Jan Lubiński; Steven A Narod; Mohammad R Akbari; Cezary Cybulski Journal: Br J Cancer Date: 2021-05-18 Impact factor: 7.640
Authors: Burcu F Darst; Xin Sheng; Rosalind A Eeles; Zsofia Kote-Jarai; David V Conti; Christopher A Haiman Journal: Eur Urol Date: 2021-05-01 Impact factor: 24.267
Authors: Anna Plym; Miklós Dióssy; Zoltan Szallasi; Oliver Sartor; Jonathan Silberstein; Isaac J Powell; Timothy R Rebbeck; Kathryn L Penney; Lorelei A Mucci; Mark M Pomerantz; Adam S Kibel Journal: JNCI Cancer Spectr Date: 2021-12-27
Authors: Amy Finch; Roderick Clark; Danny Vesprini; Justin Lorentz; Raymond H Kim; Emily Thain; Neil Fleshner; Mohammad R Akbari; Cezary Cybulski; Steven A Narod Journal: NPJ Precis Oncol Date: 2022-06-22
Authors: Anna E Harris; Veronika M Metzler; Jennifer Lothion-Roy; Dhruvika Varun; Corinne L Woodcock; Daisy B Haigh; Chantelle Endeley; Maria Haque; Michael S Toss; Mansour Alsaleem; Jenny L Persson; Lorraine J Gudas; Emad Rakha; Brian D Robinson; Francesca Khani; Laura M Martin; Jenna E Moyer; Juliette Brownlie; Srinivasan Madhusudan; Cinzia Allegrucci; Victoria H James; Catrin S Rutland; Rupert G Fray; Atara Ntekim; Simone de Brot; Nigel P Mongan; Jennie N Jeyapalan Journal: Front Endocrinol (Lausanne) Date: 2022-10-03 Impact factor: 6.055
Authors: Samantha E Greenberg; Trevor C Hunt; Jacob P Ambrose; William T Lowrance; Christopher B Dechet; Brock B O'Neil; Jonathan D Tward Journal: JCO Precis Oncol Date: 2021-03-23
Authors: Tú Nguyen-Dumont; James G Dowty; Robert J MacInnis; Jason A Steen; Moeen Riaz; Pierre-Antoine Dugué; Anne-Laure Renault; Fleur Hammet; Maryam Mahmoodi; Derrick Theys; Helen Tsimiklis; Gianluca Severi; Damien Bolton; Paul Lacaze; Robert Sebra; Eric Schadt; John McNeil; Graham G Giles; Roger L Milne; Melissa C Southey Journal: Cancers (Basel) Date: 2021-03-24 Impact factor: 6.639
Authors: Questa Karlsson; Mark N Brook; Tokhir Dadaev; Sarah Wakerell; Edward J Saunders; Kenneth Muir; David E Neal; Graham G Giles; Robert J MacInnis; Stephen N Thibodeau; Shannon K McDonnell; Lisa Cannon-Albright; Manuel R Teixeira; Paula Paulo; Marta Cardoso; Chad Huff; Donghui Li; Yu Yao; Paul Scheet; Jennifer B Permuth; Janet L Stanford; James Y Dai; Elaine A Ostrander; Olivier Cussenot; Géraldine Cancel-Tassin; Josef Hoegel; Kathleen Herkommer; Johanna Schleutker; Teuvo L J Tammela; Venkat Rathinakannan; Csilla Sipeky; Fredrik Wiklund; Henrik Grönberg; Markus Aly; William B Isaacs; Jo L Dickinson; Liesel M FitzGerald; Melvin L K Chua; Tu Nguyen-Dumont; Daniel J Schaid; Melissa C Southey; Rosalind A Eeles; Zsofia Kote-Jarai Journal: Eur Urol Oncol Date: 2021-01-09