Prediction of Breast Cancer Risk Based on Profiling With Common Genetic Variants
Nasim Mavaddat(University of Cambridge), Paul D.P. Pharoah(University of Cambridge), Kyriaki Michailidou(University of Cambridge), Jonathan P. Tyrer(University of Cambridge), Mark N. Brook(Institute of Cancer Research), Manjeet K. Bolla(University of Cambridge), Qin Wang(University of Cambridge), Joe Dennis(University of Cambridge), Alison M. Dunning(University of Cambridge), Mitul Shah(University of Cambridge), Robert Luben(University of Cambridge), Judith Brown(University of Cambridge), Stig E. Bojesen(University of Copenhagen), Børge G. Nordestgaard(University of Copenhagen), Sune F. Nielsen(University of Copenhagen), Henrik Flyger(University of Copenhagen), Kamila Czene(Cancer Research UK), Hatef Darabi(Cancer Research UK), Mikael Eriksson(Cancer Research UK), Julian Peto(University of London), Isabel dos‐Santos‐Silva(University of London), Frank Dudbridge(University of London), Nichola Johnson(Institute of Cancer Research), Marjanka K. Schmidt(Cancer Research UK), Annegien Broeks(Cancer Research UK), Senno Verhoef(Cancer Research UK), Emiel J. Rutgers(Cancer Research UK), Anthony J. Swerdlow(Institute of Cancer Research), Alan Ashworth(Institute of Cancer Research), Nick Orr(Institute of Cancer Research), Minouk J. Schoemaker(Institute of Cancer Research), Jonine D. Figueroa(National Institutes of Health), Stephen J. Chanock(National Institutes of Health), Louise A. Brinton(National Institutes of Health), Jolanta Lissowska(Cancer Research UK), Fergus J. Couch(Mayo Clinic), Janet E. Olson(Mayo Clinic), Celine M. Vachon(Mayo Clinic), V. Shane Pankratz(Mayo Clinic), Diether Lambrechts(Cancer Research UK), Hans Wildiers(Cancer Research UK), Chantal Van Ongeval(Cancer Research UK), Erik Van Limbergen(Cancer Research UK), Vessela Kristensen(University of Oslo), Grethe Grenaker Alnæs(Cancer Research UK), Silje Nord(Cancer Research UK), Anne‐Lise Børresen‐Dale(University of Oslo), Heli Nevanlinna(University of Oslo), Taru Muranen(University of Oslo), Kristiina Aittomäki(University of Helsinki), Carl Blomqvist(University of Helsinki), Jenny Chang‐Claude(University of Helsinki), Anja Rudolph(University of Helsinki), Petra Seibold(University of Helsinki), Dieter Flesch‐Janys(German Cancer Research Center), Peter A. Fasching(Universität Hamburg), Lothar Haeberle(Universität Hamburg), Arif B. Ekici(University of California, Los Angeles), Matthias W. Beckmann(Universität Hamburg), Barbara Burwinkel(Friedrich-Alexander-Universität Erlangen-Nürnberg), Frederik Marmé(German Cancer Research Center), Andreas Schneeweiß(German Cancer Research Center), Christof Sohn(Friedrich-Alexander-Universität Erlangen-Nürnberg), Amy Trentham‐Dietz(Heidelberg University), Polly A. Newcomb(University of Wisconsin–Madison), Linda Titus(Cape Town HVTN Immunology Laboratory / Hutchinson Centre Research Institute of South Africa), Kathleen M. Egan(Dartmouth College), David J. Hunter(University of South Florida), Sara Lindström(University of South Florida), Rulla M. Tamimi(Cancer Research UK), Peter Kraft(University of South Florida), Nazneen Rahman(Cancer Research UK), Clare Turnbull(Cancer Research UK), Anthony Renwick(Cancer Research UK), Sheila Seal(Mayo Clinic), Jingmei Li(Institute of Cancer Research), Jianjun Liu(Institute of Cancer Research), Keith Humphreys(Cancer Research UK), Javier Benı́tez(Agency for Science, Technology and Research), M. Pilar Zamora(Cancer Research UK), José Ignacio Arias Pérez(Cancer Research UK), Primitiva Menéndez(Cancer Research UK), Anna Jakubowska(Cancer Research UK), Jan Lubiński(Cancer Research UK), Katarzyna Jaworska–Bieniek(Cancer Research UK), Katarzyna Durda(Cancer Research UK), Natalia Bogdanova(Cancer Research UK), Natalia Antonenkova(Cancer Research UK), Thilo Dörk(Cancer Research UK), Hoda Anton‐Culver(Cancer Research UK), Susan L. Neuhausen(University of California, Irvine), Argyrios Ziogas(Cancer Research UK), Leslie Bernstein(University of California, Irvine), Peter Devilee(City Of Hope National Medical Center), Robert A.E.M. Tollenaar(Leiden University), Caroline Seynaeve(Leiden University), Christi J. van Asperen(Leiden University), Angela Cox(University of Cambridge), Simon S. Cross(Cancer Research UK), Malcolm Reed(Leiden University), Э. К. Хуснутдинова(Cancer Research UK), Marina Bermisheva(Cancer Research UK), Darya Prokofyeva(Cancer Research UK), Zalina Takhirova(Cancer Research UK), Alfons Meindl(Bashkir State University), Rita K. Schmutzler(University of Cologne), Christian Sutter(University of Cologne), Rongxi Yang(Friedrich-Alexander-Universität Erlangen-Nürnberg), Peter Schürmann(Cancer Research UK), Michael Bremer(University of Cambridge), Hans Christiansen(Cancer Research UK), Tjoung‐Won Park‐Simon(Cancer Research UK), Peter Hillemanns(Cancer Research UK), Pascal Guénel(Inserm), Thérèse Truong(Inserm), F. Ménégaux(Inserm), Marie Sanchez(Inserm), Paolo Radice(Université Paris-Saclay), Paolo Peterlongo(Cancer Research UK), Siranoush Manoukian(Cancer Research UK), Valeria Pensotti(Cancer Research UK), John L. Hopper(Cancer Research UK), Helen Tsimiklis(The University of Melbourne), Carmel Apicella(Cancer Research UK), Melissa C. Southey(The University of Melbourne), Hiltrud Brauch(The University of Melbourne), Thomas Brüning(Cancer Research UK), Yon‐Dschun Ko(German Cancer Research Center), Alice J. Sigurdson(National Institutes of Health), Michele M. Doody(University of Cambridge), Ute Hamann(Pontificia Universidad Javeriana), Diana Torres(Cancer Research UK), Hans-Ulrich Ulmer(German Cancer Research Center), Asta Försti(Guy's and St Thomas' NHS Foundation Trust), Elinor J. Sawyer(Cancer Research UK), Ian Tomlinson(Ollscoil na Gaillimhe – University of Galway), Michael J. Kerin(University of Toronto), Nicola Miller(University of Toronto), Irene L. Andrulis(University of Toronto), Julia A. Knight(University of Toronto), Gord Glendon(University of Toronto), Anna Marie Mulligan(University Health Network), Georgia Chenevix‐Trench(Cancer Research UK), Rosemary L. Balleine(The University of Sydney), Graham G. Giles(Cancer Council Victoria), Roger L. Milne(Cancer Council Victoria), Catriona McLean(Cancer Research UK), Annika Lindblom(Cancer Research UK), Sara Margolin(Cancer Research UK), Christopher A. Haiman(University of Southern California), Brian E. Henderson(University of Southern California), Fredrick R. Schumacher(University of Southern California), Loı̈c Le Marchand(Cancer Research UK), Ursula Eilber(University of Helsinki), Shan Wang‐Gohrke(Universität Ulm), Maartje J. Hooning(Cancer Research UK), Antoinette Hollestelle(Cancer Research UK), Ans M.W. van den Ouweland(Cancer Research UK), Linetta B. Koppert(Cancer Research UK), Jane Carpenter(The University of Sydney), Christine L. Clarke(The University of Sydney), Rodney J. Scott(Cancer Research UK), Arto Mannermaa(University of Eastern Finland), Vesa Kataja(University of Eastern Finland), Veli-Matti Kosma(University of Eastern Finland), Jaana M. Hartikainen(University of Eastern Finland), Hermann Brenner(German Cancer Research Center), Volker Arndt(Cancer Research UK), Christa Stegmaier(German Cancer Research Center), Aida Karina Dieffenbach(German Cancer Research Center), Robert Winqvist(Cancer Research UK), Katri Pylkäs(Cancer Research UK), Arja Jukkola‐Vuorinen(Cancer Research UK), Mervi Grip(Cancer Research UK), Kenneth Offit(Memorial Sloan Kettering Cancer Center), Joseph Vijai(Memorial Sloan Kettering Cancer Center), Mark E. Robson(Cancer Research UK), Rohini Rau‐Murthy(Cancer Research UK), Miriam Dwek(National Institutes of Health), Ruth Swann(Memorial Sloan Kettering Cancer Center), Katherine Annie Perkins(Memorial Sloan Kettering Cancer Center), Mark S. Goldberg(Cancer Research UK), France Labrèche(Cancer Research UK), Martine Dumont(Cancer Research UK), Diana M. Eccles(Cancer Research UK), William Tapper(Cancer Research UK), Sajjad Rafiq(Cancer Research UK), Esther M. John(Cancer Prevention Institute of California), Alice S. Whittemore(Cancer Prevention Institute of California), Susan Slager(University of Cambridge), Drakoulis Yannoukakos(Cancer Research UK), Amanda E. Toland(Cancer Research UK), Song Yao(Cancer Research UK), Wei Zheng(Roswell Park Comprehensive Cancer Center), Sandra L. Halverson(Roswell Park Comprehensive Cancer Center), Anna González‐Neira(Cancer Research UK), Guillermo Pita(Agency for Science, Technology and Research), M. Rosario Alonso(Agency for Science, Technology and Research), Núria Álvarez(Agency for Science, Technology and Research), Daniel Herrero(Agency for Science, Technology and Research), Daniel C. Tessier(Vanderbilt University), Daniel Vincent(Vanderbilt University), François Bacot(Vanderbilt University), Craig Luccarini(University of Cambridge), Caroline Baynes(University of Cambridge), Shahana Ahmed(University of Cambridge), Mel Maranian(University of Cambridge), Catherine S. Healey(University of Cambridge), Jacques Simard(Cancer Research UK), Per Hall(Cancer Research UK), Douglas F. Easton(University of Cambridge), Montserrat García‐Closas(Institute of Cancer Research)
Cited by 566Open Access
Abstract
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.