Prediction of breast cancer risk based on profiling with common genetic variants.

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

J Natl Cancer Inst 2015 May 8;107(5). Epub 2015 Apr 8.

Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK (NM, PDPP, KM, MKB, QW, JD, RL, JBr, DFE); Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK (PDPP, JT, AMD, MS, CL, CB, SA, MM, CSH, DFE); Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK (MNB, ASw, MJS); Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark (SEB, BGN, SFN); Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Herlev, Denmark (SEB, BGN, SFN); Faculty of Health and Medical Sciences, Copenhagen University Hospital, Copenhagen, Herlev, Denmark (SEB, BGN); Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Herlev, Denmark (HF); Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (KC, HD, ME, KH, PHa); Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK (JP, IdSS, FD); Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK (NJ, AA, NO, MGC); Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Amsterdam, the Netherlands (MKS, AB, SV, EJR); Division of Breast Cancer Research, Institute of Cancer Research, London, UK (ASw); Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD (JF, SJC, LB, ASi, MD); Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland (JLis); Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN (FJC); Department of Health Sciences Research, Mayo Clinic, Rochester, MN (JEO, CV, VSP, SS); Vesalius Research Center, VIB, Leuven, Belgium (DL); Laboratory for Translational Genetics, Department of Oncology, University of

Background: Data for multiple common susceptibility alleles for breast cancer may be combined to identify women at different levels of breast cancer risk. Such stratification could guide preventive and screening strategies. However, empirical evidence for genetic risk stratification is lacking.

Methods: We investigated the value of using 77 breast cancer-associated single nucleotide polymorphisms (SNPs) for risk stratification, in a study of 33 673 breast cancer cases and 33 381 control women of European origin. We tested all possible pair-wise multiplicative interactions and constructed a 77-SNP polygenic risk score (PRS) for breast cancer overall and by estrogen receptor (ER) status. Absolute risks of breast cancer by PRS were derived from relative risk estimates and UK incidence and mortality rates.

Results: There was no strong evidence for departure from a multiplicative model for any SNP pair. Women in the highest 1% of the PRS had a three-fold increased risk of developing breast cancer compared with women in the middle quintile (odds ratio [OR] = 3.36, 95% confidence interval [CI] = 2.95 to 3.83). The ORs for ER-positive and ER-negative disease were 3.73 (95% CI = 3.24 to 4.30) and 2.80 (95% CI = 2.26 to 3.46), respectively. Lifetime risk of breast cancer for women in the lowest and highest quintiles of the PRS were 5.2% and 16.6% for a woman without family history, and 8.6% and 24.4% for a woman with a first-degree family history of breast cancer.

Conclusions: The PRS stratifies breast cancer risk in women both with and without a family history of breast cancer. The observed level of risk discrimination could inform targeted screening and prevention strategies. Further discrimination may be achievable through combining the PRS with lifestyle/environmental factors, although these were not considered in this report.

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May 2015
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