Mark E Robson1,2,3, Anne S Reiner2,4, Jennifer D Brooks5, Patrick J Concannon6, Esther M John7,8, Lene Mellemkjaer9, Leslie Bernstein10, Kathleen E Malone11, Julia A Knight5,12, Charles F Lynch13, Meghan Woods4,2, Xiaolin Liang4,2, Robert W Haile8,14, David J Duggan15, Roy E Shore16, Susan A Smith17, Duncan C Thomas18,19, Daniel O Stram19,20, Jonine L Bernstein4,2. 1. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 2. Memorial Sloan Kettering Cancer Center, New York, NY, USA. 3. Department of Medicine, Weill Cornell Medical College, Cornell University, New York, NY, USA. 4. Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York,NY, USA. 5. Epidemiology Division, University of Toronto, Dalla Lana School of Public Health Sciences, Toronto, ON, Canada. 6. Genetics Institute, University of Florida, Gainesville, FL, USA. 7. Division of Epidemiology, Department of Health Research and Policy, Cancer Prevention Institute of California, Fremont, CA, USA. 8. Stanford School of Medicine, Stanford, CA, USA. 9. Danish Cancer Society, Copenhagen, Denmark. 10. Division of Cancer Etiology, Department of Population Sciences, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA. 11. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. 12. Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada. 13. Department of Epidemiology, University of Iowa, Iowa City, IA, USA. 14. Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University, California. 15. Integrated Cancer Genomics Division, Translational Genomics Research Institute (TGen), Phoenix, AZ, USA. 16. Department of Population Health, New York University, New York, NY, USA. 17. Department of Radiation Physics, University of Texas, MD Anderson Cancer Center, Houston, TX, USA. 18. Division of Biostatistics, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA. 19. Division of Biostatistics and Genetic Epidemiology, University of Southern California, Los Angeles, CA, USA. 20. Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA, USA.
Abstract
Background: Women with unilateral breast cancer (UBC) are at risk of developing a subsequent contralateral breast cancer (CBC). Common variants are associated with breast cancer risk. Whether these influence CBC risk is unknown. Methods: Participants were breast cancer cases from the population-based Women's Environmental Cancer and Radiation Epidemiology (WECARE) Study. Sixty-seven established breast cancer risk loci were genotyped directly or by imputation in 1459 case subjects with CBC and 2126 UBC control subjects. An unweighted polygenic risk score (PRS) was created by summing the number of risk alleles for each directly genotyped single nucleotide polymorphism (SNP), or for imputed loci, the imputed dosage. A weighted PRS was calculated similarly, but where each SNP's contribution was weighted by the published per-allele log odds ratio. Unweighted and weighted polygenic risk scores and CBC risk were modeled using conditional logistic regression. Cumulative CBC risk was estimated and benchmarked using Surveillance, Epidemiology, and End Results population incidence rates. Results: Both unweighted and weighted PRS were statistically significantly associated with CBC risk. The adjusted risk ratio of CBC in women in the upper quartile of unweighted PRS compared with the lowest quartile was 1.63 (95% confidence interval [CI] = 1.33 to 2.00). The estimated 10-year cumulative risk for women in the upper quartile of the unweighted PRS was 7.4% (95% CI = 6.0% to 9.1%). For women in the upper quartile of the weighted PRS, the risk ratio for CBC was 1.75 (95% CI = 1.41 to 2.18) compared with women in the lowest quartile. There was no statistically significant heterogeneity by age, treatment (radiation therapy dose, tamoxifen, chemotherapy), estrogen receptor status of the first primary, histology of the first primary, length of at-risk period for CBC, or breast cancer family history. Conclusions: Common genomic variants associated with the development of first primary breast cancer are also associated with the development of CBC; the risk is strongest among those who carry more risk alleles.
Background: Women with unilateral breast cancer (UBC) are at risk of developing a subsequent contralateral breast cancer (CBC). Common variants are associated with breast cancer risk. Whether these influence CBC risk is unknown. Methods:Participants were breast cancer cases from the population-based Women's Environmental Cancer and Radiation Epidemiology (WECARE) Study. Sixty-seven established breast cancer risk loci were genotyped directly or by imputation in 1459 case subjects with CBC and 2126 UBC control subjects. An unweighted polygenic risk score (PRS) was created by summing the number of risk alleles for each directly genotyped single nucleotide polymorphism (SNP), or for imputed loci, the imputed dosage. A weighted PRS was calculated similarly, but where each SNP's contribution was weighted by the published per-allele log odds ratio. Unweighted and weighted polygenic risk scores and CBC risk were modeled using conditional logistic regression. Cumulative CBC risk was estimated and benchmarked using Surveillance, Epidemiology, and End Results population incidence rates. Results: Both unweighted and weighted PRS were statistically significantly associated with CBC risk. The adjusted risk ratio of CBC in women in the upper quartile of unweighted PRS compared with the lowest quartile was 1.63 (95% confidence interval [CI] = 1.33 to 2.00). The estimated 10-year cumulative risk for women in the upper quartile of the unweighted PRS was 7.4% (95% CI = 6.0% to 9.1%). For women in the upper quartile of the weighted PRS, the risk ratio for CBC was 1.75 (95% CI = 1.41 to 2.18) compared with women in the lowest quartile. There was no statistically significant heterogeneity by age, treatment (radiation therapy dose, tamoxifen, chemotherapy), estrogen receptor status of the first primary, histology of the first primary, length of at-risk period for CBC, or breast cancer family history. Conclusions: Common genomic variants associated with the development of first primary breast cancer are also associated with the development of CBC; the risk is strongest among those who carry more risk alleles.
Authors: Alkes L Price; Nick J Patterson; Robert M Plenge; Michael E Weinblatt; Nancy A Shadick; David Reich Journal: Nat Genet Date: 2006-07-23 Impact factor: 38.330
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Authors: Nasim Mavaddat; Paul D P Pharoah; Kyriaki Michailidou; Jonathan Tyrer; Mark N Brook; Manjeet K Bolla; Qin Wang; Joe Dennis; Alison M Dunning; Mitul Shah; Robert Luben; Judith Brown; Stig E Bojesen; Børge G Nordestgaard; Sune F Nielsen; Henrik Flyger; Kamila Czene; Hatef Darabi; Mikael Eriksson; Julian Peto; Isabel Dos-Santos-Silva; Frank Dudbridge; Nichola Johnson; Marjanka K Schmidt; Annegien Broeks; Senno Verhoef; Emiel J Rutgers; Anthony Swerdlow; Alan Ashworth; Nick Orr; Minouk J Schoemaker; Jonine Figueroa; Stephen J Chanock; Louise Brinton; Jolanta Lissowska; Fergus J Couch; Janet E Olson; Celine Vachon; Vernon S Pankratz; Diether Lambrechts; Hans Wildiers; Chantal Van Ongeval; Erik van Limbergen; Vessela Kristensen; Grethe Grenaker Alnæs; Silje Nord; Anne-Lise Borresen-Dale; Heli Nevanlinna; Taru A Muranen; Kristiina Aittomäki; Carl Blomqvist; Jenny Chang-Claude; Anja Rudolph; Petra Seibold; Dieter Flesch-Janys; Peter A Fasching; Lothar Haeberle; Arif B Ekici; Matthias W Beckmann; Barbara Burwinkel; Frederik Marme; Andreas Schneeweiss; Christof Sohn; Amy Trentham-Dietz; Polly Newcomb; Linda Titus; Kathleen M Egan; David J Hunter; Sara Lindstrom; Rulla M Tamimi; Peter Kraft; Nazneen Rahman; Clare Turnbull; Anthony Renwick; Sheila Seal; Jingmei Li; Jianjun Liu; Keith Humphreys; Javier Benitez; M Pilar Zamora; Jose Ignacio Arias Perez; Primitiva Menéndez; Anna Jakubowska; Jan Lubinski; Katarzyna Jaworska-Bieniek; Katarzyna Durda; Natalia V Bogdanova; Natalia N Antonenkova; Thilo Dörk; Hoda Anton-Culver; Susan L Neuhausen; Argyrios Ziogas; Leslie Bernstein; Peter Devilee; Robert A E M Tollenaar; Caroline Seynaeve; Christi J van Asperen; Angela Cox; Simon S Cross; Malcolm W R Reed; Elza Khusnutdinova; Marina Bermisheva; Darya Prokofyeva; Zalina Takhirova; Alfons Meindl; Rita K Schmutzler; Christian Sutter; Rongxi Yang; Peter Schürmann; Michael Bremer; Hans Christiansen; Tjoung-Won Park-Simon; Peter Hillemanns; Pascal Guénel; Thérèse Truong; Florence Menegaux; Marie Sanchez; Paolo Radice; Paolo Peterlongo; Siranoush Manoukian; Valeria Pensotti; John L Hopper; Helen Tsimiklis; Carmel Apicella; Melissa C Southey; Hiltrud Brauch; Thomas Brüning; Yon-Dschun Ko; Alice J Sigurdson; Michele M Doody; Ute Hamann; Diana Torres; Hans-Ulrich Ulmer; Asta Försti; Elinor J Sawyer; Ian Tomlinson; Michael J Kerin; Nicola Miller; Irene L Andrulis; Julia A Knight; Gord Glendon; Anna Marie Mulligan; Georgia Chenevix-Trench; Rosemary Balleine; Graham G Giles; Roger L Milne; Catriona McLean; Annika Lindblom; Sara Margolin; Christopher A Haiman; Brian E Henderson; Fredrick Schumacher; Loic Le Marchand; Ursula Eilber; Shan Wang-Gohrke; Maartje J Hooning; Antoinette Hollestelle; Ans M W van den Ouweland; Linetta B Koppert; Jane Carpenter; Christine Clarke; Rodney Scott; Arto Mannermaa; Vesa Kataja; Veli-Matti Kosma; Jaana M Hartikainen; Hermann Brenner; Volker Arndt; Christa Stegmaier; Aida Karina Dieffenbach; Robert Winqvist; Katri Pylkäs; Arja Jukkola-Vuorinen; Mervi Grip; Kenneth Offit; Joseph Vijai; Mark Robson; Rohini Rau-Murthy; Miriam Dwek; Ruth Swann; Katherine Annie Perkins; Mark S Goldberg; France Labrèche; Martine Dumont; Diana M Eccles; William J Tapper; Sajjad Rafiq; Esther M John; Alice S Whittemore; Susan Slager; Drakoulis Yannoukakos; Amanda E Toland; Song Yao; Wei Zheng; Sandra L Halverson; Anna González-Neira; Guillermo Pita; M Rosario Alonso; Nuria Álvarez; Daniel Herrero; Daniel C Tessier; Daniel Vincent; Francois Bacot; Craig Luccarini; Caroline Baynes; Shahana Ahmed; Mel Maranian; Catherine S Healey; Jacques Simard; Per Hall; Douglas F Easton; Montserrat Garcia-Closas Journal: J Natl Cancer Inst Date: 2015-04-08 Impact factor: 13.506
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