Burcu F Darst1, Xin Sheng2, Rosalind A Eeles3, Zsofia Kote-Jarai4, David V Conti2, Christopher A Haiman2. 1. Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, USA. Electronic address: bdarst@usc.edu. 2. Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, USA. 3. The Institute of Cancer Research, London, UK; The Royal Marsden NHS Foundation Trust, London, UK. 4. The Institute of Cancer Research, London, UK.
Abstract
Although prostate cancer is known to have a strong genetic basis and is influenced by both common and rare variants, the ability to investigate the combined effect of such genetic risk factors has been limited to date. We conducted an investigation of 81 094 men from the UK Biobank, including 3568 prostate cancer cases, to examine the combined effect of rare pathogenic/likely pathogenic/deleterious (P/LP/D) germline variants and common prostate cancer risk variants, measured using a polygenic risk score (PRS), on prostate cancer risk. The absolute risk of prostate cancer for HOXB13, BRCA2, ATM, and CHEK2 P/LP/D carriers ranged from 9% to 56%, and the absolute risk in noncarriers ranged from 2% to 31%, by age 85 yr, for men in the lowest and highest PRS decile, respectively. The high-penetrant HOXB13 G84E prostate cancer risk variant was most common in cases in the lowest PRS quintile (4.4%) and least common in cases in the highest PRS quintile (0.5%; p = 0.005), whereas there was no statistically significant difference in frequencies by PRS in controls. While rare and common variants strongly and distinctly influence prostate cancer onset, consideration of rare and common variants in conjunction will lead to more precise estimates of a man's lifetime risk of prostate cancer. PATIENT SUMMARY: We found that the risk of prostate cancer conveyed by rare variants could vary depending on an individual's genetic profile of common risk variants. This implies that in order to comprehensively assess genetic risk of prostate cancer, it is important to consider both rare and common variants.
Although prostate cancer is known to have a strong genetic basis and is influenced by both common and rare variants, the ability to investigate the combined effect of such genetic risk factors has been limited to date. We conducted an investigation of 81 094 men from the UK Biobank, including 3568 prostate cancer cases, to examine the combined effect of rare pathogenic/likely pathogenic/deleterious (P/LP/D) germline variants and common prostate cancer risk variants, measured using a polygenic risk score (PRS), on prostate cancer risk. The absolute risk of prostate cancer for HOXB13, BRCA2, ATM, and CHEK2 P/LP/D carriers ranged from 9% to 56%, and the absolute risk in noncarriers ranged from 2% to 31%, by age 85 yr, for men in the lowest and highest PRS decile, respectively. The high-penetrant HOXB13 G84E prostate cancer risk variant was most common in cases in the lowest PRS quintile (4.4%) and least common in cases in the highest PRS quintile (0.5%; p = 0.005), whereas there was no statistically significant difference in frequencies by PRS in controls. While rare and common variants strongly and distinctly influence prostate cancer onset, consideration of rare and common variants in conjunction will lead to more precise estimates of a man's lifetime risk of prostate cancer. PATIENT SUMMARY: We found that the risk of prostate cancer conveyed by rare variants could vary depending on an individual's genetic profile of common risk variants. This implies that in order to comprehensively assess genetic risk of prostate cancer, it is important to consider both rare and common variants.
Authors: Dalin Li; Juan Pablo Lewinger; William J Gauderman; Cassandra Elizabeth Murcray; David Conti Journal: Genet Epidemiol Date: 2011-09-15 Impact factor: 2.135
Authors: Robert Karlsson; Markus Aly; Mark Clements; Lilly Zheng; Jan Adolfsson; Jianfeng Xu; Henrik Grönberg; Fredrik Wiklund Journal: Eur Urol Date: 2012-07-20 Impact factor: 20.096
Authors: Marco Matejcic; Yesha Patel; Jenna Lilyquist; Chunling Hu; Kun Y Lee; Rohan D Gnanaolivu; Steven N Hart; Eric C Polley; Siddhartha Yadav; Nicholas J Boddicker; Raed Samara; Lucy Xia; Xin Sheng; Alexander Lubmawa; Vicky Kiddu; Benon Masaba; Dan Namuguzi; George Mutema; Kuteesa Job; Dabanja M Henry; Sue A Ingles; Lynne Wilkens; Loic Le Marchand; Stephen Watya; Fergus J Couch; David V Conti; Christopher A Haiman Journal: JCO Precis Oncol Date: 2020-01-31
Authors: Z Kote-Jarai; C Mikropoulos; D A Leongamornlert; T Dadaev; M Tymrakiewicz; E J Saunders; M Jones; S Jugurnauth-Little; K Govindasami; M Guy; F C Hamdy; J L Donovan; D E Neal; J A Lane; D Dearnaley; R A Wilkinson; E J Sawyer; A Morgan; A C Antoniou; R A Eeles Journal: Ann Oncol Date: 2015-01-16 Impact factor: 32.976
Authors: Zhuqing Shi; Elizabeth A Platz; Jun Wei; Rong Na; Richard J Fantus; Chi-Hsiung Wang; Scott E Eggener; Peter J Hulick; David Duggan; S Lilly Zheng; Kathleen A Cooney; William B Isaacs; Brian T Helfand; Jianfeng Xu Journal: Eur Urol Date: 2020-11-28 Impact factor: 20.096
Authors: Shannon Gallagher; Elisha Hughes; Susanne Wagner; Placede Tshiaba; Eric Rosenthal; Benjamin B Roa; Allison W Kurian; Susan M Domchek; Judy Garber; Johnathan Lancaster; Jeffrey N Weitzel; Alexander Gutin; Jerry S Lanchbury; Mark Robson Journal: JAMA Netw Open Date: 2020-07-01
Authors: David V Conti; Burcu F Darst; Lilit C Moss; Edward J Saunders; Xin Sheng; Alisha Chou; Fredrick R Schumacher; Ali Amin Al Olama; Sara Benlloch; Tokhir Dadaev; Mark N Brook; Ali Sahimi; Thomas J Hoffmann; Atushi Takahashi; Koichi Matsuda; Yukihide Momozawa; Masashi Fujita; Kenneth Muir; Artitaya Lophatananon; Peggy Wan; Loic Le Marchand; Lynne R Wilkens; Victoria L Stevens; Susan M Gapstur; Brian D Carter; Johanna Schleutker; Teuvo L J Tammela; Csilla Sipeky; Anssi Auvinen; Graham G Giles; Melissa C Southey; Robert J MacInnis; Cezary Cybulski; Dominika Wokołorczyk; Jan Lubiński; David E Neal; Jenny L Donovan; Freddie C Hamdy; Richard M Martin; Børge G Nordestgaard; Sune F Nielsen; Maren Weischer; Stig E Bojesen; Martin Andreas Røder; Peter Iversen; Jyotsna Batra; Suzanne Chambers; Leire Moya; Lisa Horvath; Judith A Clements; Wayne Tilley; Gail P Risbridger; Henrik Gronberg; Markus Aly; Robert Szulkin; Martin Eklund; Tobias Nordström; Nora Pashayan; Alison M Dunning; Maya Ghoussaini; Ruth C Travis; Tim J Key; Elio Riboli; Jong Y Park; Thomas A Sellers; Hui-Yi Lin; Demetrius Albanes; Stephanie J Weinstein; Lorelei A Mucci; Edward Giovannucci; Sara Lindstrom; Peter Kraft; David J Hunter; Kathryn L Penney; Constance Turman; Catherine M Tangen; Phyllis J Goodman; Ian M Thompson; Robert J Hamilton; Neil E Fleshner; Antonio Finelli; Marie-Élise Parent; Janet L Stanford; Elaine A Ostrander; Milan S Geybels; Stella Koutros; Laura E Beane Freeman; Meir Stampfer; Alicja Wolk; Niclas Håkansson; Gerald L Andriole; Robert N Hoover; Mitchell J Machiela; Karina Dalsgaard Sørensen; Michael Borre; William J Blot; Wei Zheng; Edward D Yeboah; James E Mensah; Yong-Jie Lu; Hong-Wei Zhang; Ninghan Feng; Xueying Mao; Yudong Wu; Shan-Chao Zhao; Zan Sun; Stephen N Thibodeau; Shannon K McDonnell; Daniel J Schaid; Catharine M L West; Neil Burnet; Gill Barnett; Christiane Maier; Thomas Schnoeller; Manuel Luedeke; Adam S Kibel; Bettina F Drake; Olivier Cussenot; Géraldine Cancel-Tassin; Florence Menegaux; Thérèse Truong; Yves Akoli Koudou; Esther M John; Eli Marie Grindedal; Lovise Maehle; Kay-Tee Khaw; Sue A Ingles; Mariana C Stern; Ana Vega; Antonio Gómez-Caamaño; Laura Fachal; Barry S Rosenstein; Sarah L Kerns; Harry Ostrer; Manuel R Teixeira; Paula Paulo; Andreia Brandão; Stephen Watya; Alexander Lubwama; Jeannette T Bensen; Elizabeth T H Fontham; James Mohler; Jack A Taylor; Manolis Kogevinas; Javier Llorca; Gemma Castaño-Vinyals; Lisa Cannon-Albright; Craig C Teerlink; Chad D Huff; Sara S Strom; Luc Multigner; Pascal Blanchet; Laurent Brureau; Radka Kaneva; Chavdar Slavov; Vanio Mitev; Robin J Leach; Brandi Weaver; Hermann Brenner; Katarina Cuk; Bernd Holleczek; Kai-Uwe Saum; Eric A Klein; Ann W Hsing; Rick A Kittles; Adam B Murphy; Christopher J Logothetis; Jeri Kim; Susan L Neuhausen; Linda Steele; Yuan Chun Ding; William B Isaacs; Barbara Nemesure; Anselm J M Hennis; John Carpten; Hardev Pandha; Agnieszka Michael; Kim De Ruyck; Gert De Meerleer; Piet Ost; Jianfeng Xu; Azad Razack; Jasmine Lim; Soo-Hwang Teo; Lisa F Newcomb; Daniel W Lin; Jay H Fowke; Christine Neslund-Dudas; Benjamin A Rybicki; Marija Gamulin; Davor Lessel; Tomislav Kulis; Nawaid Usmani; Sandeep Singhal; Matthew Parliament; Frank Claessens; Steven Joniau; Thomas Van den Broeck; Manuela Gago-Dominguez; Jose Esteban Castelao; Maria Elena Martinez; Samantha Larkin; Paul A Townsend; Claire Aukim-Hastie; William S Bush; Melinda C Aldrich; Dana C Crawford; Shiv Srivastava; Jennifer C Cullen; Gyorgy Petrovics; Graham Casey; Monique J Roobol; Guido Jenster; Ron H N van Schaik; Jennifer J Hu; Maureen Sanderson; Rohit Varma; Roberta McKean-Cowdin; Mina Torres; Nicholas Mancuso; Sonja I Berndt; Stephen K Van Den Eeden; Douglas F Easton; Stephen J Chanock; Michael B Cook; Fredrik Wiklund; Hidewaki Nakagawa; John S Witte; Rosalind A Eeles; Zsofia Kote-Jarai; Christopher A Haiman Journal: Nat Genet Date: 2021-01-04 Impact factor: 38.330
Authors: Konrad J Karczewski; Laurent C Francioli; Grace Tiao; Beryl B Cummings; Jessica Alföldi; Qingbo Wang; Ryan L Collins; Kristen M Laricchia; Andrea Ganna; Daniel P Birnbaum; Laura D Gauthier; Harrison Brand; Matthew Solomonson; Nicholas A Watts; Daniel Rhodes; Moriel Singer-Berk; Eleina M England; Eleanor G Seaby; Jack A Kosmicki; Raymond K Walters; Katherine Tashman; Yossi Farjoun; Eric Banks; Timothy Poterba; Arcturus Wang; Cotton Seed; Nicola Whiffin; Jessica X Chong; Kaitlin E Samocha; Emma Pierce-Hoffman; Zachary Zappala; Anne H O'Donnell-Luria; Eric Vallabh Minikel; Ben Weisburd; Monkol Lek; James S Ware; Christopher Vittal; Irina M Armean; Louis Bergelson; Kristian Cibulskis; Kristen M Connolly; Miguel Covarrubias; Stacey Donnelly; Steven Ferriera; Stacey Gabriel; Jeff Gentry; Namrata Gupta; Thibault Jeandet; Diane Kaplan; Christopher Llanwarne; Ruchi Munshi; Sam Novod; Nikelle Petrillo; David Roazen; Valentin Ruano-Rubio; Andrea Saltzman; Molly Schleicher; Jose Soto; Kathleen Tibbetts; Charlotte Tolonen; Gordon Wade; Michael E Talkowski; Benjamin M Neale; Mark J Daly; Daniel G MacArthur Journal: Nature Date: 2020-05-27 Impact factor: 69.504
Authors: Lauren A Stalbow; Michael H Preuss; Roelof A J Smit; Nathalie Chami; Lise Bjørkhaug; Ingvild Aukrust; Anna L Gloyn; Ruth J F Loos Journal: Diabetologia Date: 2022-10-11 Impact factor: 10.460
Authors: Xiaoyu Song; Meng Ru; Zoe Steinsnyder; Kaitlyn Tkachuk; Ryan P Kopp; John Sullivan; Zeynep H Gümüş; Kenneth Offit; Vijai Joseph; Robert J Klein Journal: Cancer Epidemiol Biomarkers Prev Date: 2022-07-01 Impact factor: 4.090
Authors: Zhe Wang; Shing Wan Choi; Nathalie Chami; Eric Boerwinkle; Myriam Fornage; Susan Redline; Joshua C Bis; Jennifer A Brody; Bruce M Psaty; Wonji Kim; Merry-Lynn N McDonald; Elizabeth A Regan; Edwin K Silverman; Ching-Ti Liu; Ramachandran S Vasan; Rita R Kalyani; Rasika A Mathias; Lisa R Yanek; Donna K Arnett; Anne E Justice; Kari E North; Robert Kaplan; Susan R Heckbert; Mariza de Andrade; Xiuqing Guo; Leslie A Lange; Stephen S Rich; Jerome I Rotter; Patrick T Ellinor; Steven A Lubitz; John Blangero; M Benjamin Shoemaker; Dawood Darbar; Mark T Gladwin; Christine M Albert; Daniel I Chasman; Rebecca D Jackson; Charles Kooperberg; Alexander P Reiner; Paul F O'Reilly; Ruth J F Loos Journal: Front Endocrinol (Lausanne) Date: 2022-05-03 Impact factor: 6.055