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Prediction of Breast Cancer Risk Based on Profiling With Common Genetic Variants
Prediction of Breast Cancer Risk Based on Profiling With Common Genetic Variants
- 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* and
- Montserrat Garcia-Closas*
- Affiliations of authors: 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 Leuven, Leuven, Belgium (DL); Department of General Medical Oncology, University Hospitals Leuven, and Department of Oncology, KU Leuven, Leuven, Belgium (HW); Department of Radiation Oncology, University Hospital Gasthuisberg, Leuven, Belgium (EVL); Department of Radiology, University Hospital Gasthuisberg, Leuven, Belgium (CVO); Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, Oslo, Norway (VK, GGA, SN, ALBD); Institute of Clinical Medicine, University of Oslo, Oslo, Norway (VK, ALBD); Department of Clinical Molecular Biology, University of Oslo, Oslo, Norway (VK); Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, HUS, Finland (HN, TAM); Department of Clinical Genetics, University of Helsinki and Helsinki University Central Hospital, Helsinki, HUS, Finland (KA); Department of Oncology, University of Helsinki and Helsinki University Central Hospital, Helsinki, HUS, Finland (CB); Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany (JCC, AR, PS, UE); Department of Cancer Epidemiology/Clinical Cancer Registry, University Clinic Hamburg-Eppendorf, Hamburg, Germany (DFJ); University Breast Center Franconia, Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany (PAF, LH, MWB); David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, CA (PAF); Institute of Human Genetics, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany (ABE); Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany (BB, FM, ASc, CSohn, RY); Molecular Epidemiology Group, German Cancer Research Center, Heidelberg, Germany (BB, RY); National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany (FM, ASc); University of Wisconsin Carbone Cancer Center, Madison, WI (ATD, PN); Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA (PN); Geisel School of Medicine at Dartmouth, Hanover, NH (LT); Division of Population Sciences, Moffitt Cancer Center & Research Institute, Tampa, FL (KE); Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health,Boston, MA (DJH, SL, PK); Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA (DJH, SL, RMT, PK); Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA (RMT); Section of Cancer Genetics, Institute of Cancer Research, London, UK (NR, CT, AR, SS); Human Genetics Division, Genome Institute of Singapore, Singapore (JLi, JLiu); Human Genotyping-CEGEN Unit, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Madrid, Spain (JBe, AGN, GP, MRA, NA, DH); Centro de Investigación en Red de Enfermedades Raras, Valencia, Spain (JBe); Servicio de Oncología Médica, Hospital Universitario La Paz, Madrid, Spain (MPZ); Servicio de Cirugía General y Especialidades, Hospital Monte Naranco, Oviedo, Spain (JIAP); Servicio de Anatomía Patológica, Hospital Monte Naranco, Oviedo, Spain (PM); Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland (AJ, JLu, KJB, KD); Department of Obstetrics and Gynaecology, Hannover Medical School, Hannover, Germany (NVB, TD, PS, TWPS, PHi); Department of Radiation Oncology, Hannover Medical School, Hannover, Germany (NVB, MB, HC); NN Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus (NNA); Department of Epidemiology, University of California Irvine, Irvine, CA (HAC, AZ); Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA (SLN, LB); Department of Human Genetics and Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands (PD); Department of Surgical Oncology, Leiden University Medical Center, Leiden, the Netherlands (RAEMT); Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands (CJvA); Sheffield Cancer Research, Department of Oncology, University of Sheffield, UK (AC, MWRR); Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK (SSC); Institute of Biochemistry and Genetics, Ufa Scientific Center of Russian Academy of Sciences, Ufa, Russia (EK, MB, ZT); Department of Genetics and Fundamental Medicine of Bashkir State University, Ufa, Russia (EK, DP); Division of Gynaecology and Obstetrics, Technische Universität München, Munich, Germany (AMe); Center for Hereditary Breast and Ovarian Cancer, University Hospital Cologne, Cologne, Germany (RKS); Center for Integrated Oncology, University Hospital Cologne, Cologne, Germany (RKS); Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany (RKS); Institute of Human Genetics, University Heidelberg, Heidelberg, Germany (CSutter); National Institute of Health and Medical Research, Center for Research in Epidemiology and Population Health, U1018, Environmental Epidemiology of Cancer, Villejuif, France (PG, TT, FM, MS); University Paris-Sud, Villejuif, France (PG, TT, FM, MS); Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy (PR); IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy (PP, VP); Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy (SM); Cogentech Cancer Genetic Test Laboratory, Milan, Italy (VP); Centre for Epidemiology & Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia (JLH, CA, GGG, RLM); Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia (HT, MCS); Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany, for the GENICA Network (HB); University of Tübingen, Tübingen, Germany, for the GENICA Network (HB); German Cancer Consortium, German Cancer Research Center (DKFZ), Heidelberg, Germany (HBra, HBre, AKD); Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr-Universität Bochum (IPA), Germany, for the GENICA Network (TB); Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany, for the GENICA Network (YDK); Molecular Genetics of Breast Cancer, German Cancer Research Center, Heidelberg, Germany, for the GENICA Network (UH); Institute of Human Genetics, Pontificia Universidad Javeriana, Bogota, Colombia (DT); Frauenklinik der Stadtklinik Baden-Baden, Baden-Baden, Germany (HUU); Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany (AF); Center for Primary Health Care Research, University of Lund, Malmö, Sweden (AF); Division of Cancer Studies, Kings College London, Guy’s Hospital, London, UK (EJS); Wellcome Trust Centre for Human Genetics and Oxford Biomedical Research Centre, University of Oxford, Oxford, UK (IT); Clinical Science Institute, University Hospital Galway, Galway, Ireland (MJK, NM); Ontario Cancer Genetics Network, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada (ILA, GG); Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada (ILA); Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada (JAK); Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada (JAK); Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada (AMM); Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada (AMM); Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia, for the Australian Ovarian Cancer Study Group (GCT); Peter MacCallum Cancer Center, Melbourne, Victoria, Australia, for kConFab Investigators and the Australian Ovarian Cancer Study Group; Westmead Millenium Institute for Medical Research, University of Sydney, Sydney, NSW, Australia (RB, CC); Western Sydney and Nepean Blue Mountains Local Health Districts, Sydney, Australia (RB); Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia (GGG, RLM); Anatomical Pathology, The Alfred Hospital, Melbourne, Victoria, Australia (CM); Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden (AL); Department of Oncology - Pathology, Karolinska Institutet, Stockholm, Sweden (SM); Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA (CAH, BEH, FS); Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI (LLM); Department of Obstetrics and Gynecology, University of Ulm, Ulm, Germany (SWG); Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, the Netherlands (MJH, AH, CS); Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands (AMWvdO); Department of Surgical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, the Netherlands (LBK); Australian Breast Cancer Tissue Bank, Westmead Millennium Institute, University of Sydney, Sydney, NSW, Australia, for the ABCTB Investigators (JC); Division of Genetics, Hunter Area Pathology Service and University of Newcastle, Callaghan, NSW, Australia (RSc); School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine (AMa, VMK, JMH); Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland (AMa, VMK, JMH); Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland (AMa, VMK, JMH); Cancer Center, Kuopio University Hospital, Kuopio, Finland, and Jyvaskyla Central Hospital, Jyvaskyla, Finland (VK); Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany (HB, VA, AKD); Saarland Cancer Registry, Saarbrücken, Germany (CStegmaier); Laboratory of Cancer Genetics and Tumor Biology, Department of Clinical Chemistry and Biocenter Oulu, University of Oulu, Northern Finland Laboratory Centre NordLab, Oulu, Finland (RW, KP); Department of Oncology, Oulu University Hospital, University of Oulu, Oulu, Finland (AJV); Department of Surgery, Oulu University Hospital, University of Oulu, Oulu, Finland (MG); Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY (KO, JV, MR, RRM); Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY (KO, JV); Department of Molecular and Applied Biosciences, Faculty of Science and Technology, University of Westminster, London, UK (MDw, RSw, KAP); Department of Medicine, McGill University, Montreal, Quebec, Canada (MSG); Division of Clinical Epidemiology, McGill University Health Centre, Royal Victoria Hospital, Montreal, Quebec, Canada (MSG); Département de médecine sociale et préventive, Département de santé environnementale et santé au travail, Université de Montréal, Montreal, Quebec, Canada (FL); Cancer Genomics Laboratory for Genomics Centre, Centre Hospitalier Universitaire de Québec Research Centre and Laval University, Québec City, Quebec, Canada (MDu, JS); Faculty of Medicine, University of Southampton, UK (DME, WJT, SR); Cancer Prevention Institute of California, Fremont, CA (EMJ); Department of Health Research and Policy Stanford University School of Medicine Stanford CA (EMJ, ASW); Molecular Diagnostics Laboratory, IRRP, National Centre for Scientific Research “Demokritos”, Aghia Paraskevi Attikis, Athens, Greece (DY); Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH (AET); Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY (SY); Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN (WZ, SLH); McGill University and Génome Québec Innovation Centre, Montréal, Québec, Canada (DCT, DV, FB).
- ↵*Authors contributed equally to this work.
- Correspondence to: Nasim Mavaddat, MBBS, PhD, PhD, Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway Cambridge, CB1 8RN, UK (e-mail:nm274@medschl.cam.ac.uk).
- Received March 28, 2014.
- Revision received December 1, 2014.
- Accepted January 26, 2015.
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.
Breast cancer is the most common cancer among Western women, with approximately 1.67 million cases diagnosed annually worldwide (
1). Strategies such as endocrine risk–reducing medication and early detection by breast cancer screening can reduce the burden of disease but have disadvantages including side effects, overdiagnosis, and increased cost (
2–4). Stratification of women according to the risk of developing breast cancer could improve risk reduction and screening strategies by targeting those most likely to benefit (
5–8).
Both genetic and lifestyle factors are implicated in the aetiology of breast cancer. Women with a history of breast cancer in a first-degree relative are at approximately two-fold higher risk than women without a family history (
9). Rare high-risk mutations particularly in the
BRCA1 and
BRCA2 genes explain less than 20% of the two-fold familial relative risk (FRR) (
10) and account for a small proportion of breast cancer cases in the general population. Low frequency variants conferring intermediate risk, such as those in
CHEK2,
ATM, and
PALB2, explain 2% to 5% of the FRR. Genome-wide association studies (GWAS) have led to the discovery of multiple common, low-risk variants (single nucleotide polymorphisms [SNPs]) associated with breast cancer risk (
11), many of which are differentially associated by estrogen receptor (ER) status (
12,
13). Recently, new risk-associated variants have been identified in a large-scale replication study conducted by the Breast Cancer Association Consortium (BCAC) as part of the Collaborative Oncological Gene-Environment Study (COGS). SNPs were genotyped in over 40 000 breast cancer cases and 40 000 control women, using a custom array (iCOGS). This experiment increased the number of SNPs robustly associated with breast cancer from 27 to more than 70 and identified additional variants specific to ER-negative breast cancer (
14–17).
Risks conferred by SNPs are not sufficiently large to be useful in risk prediction individually. However, the combined effect of multiple SNPs could achieve a degree of risk discrimination that is useful for population-based programmes of breast cancer prevention and early detection (
8,
18). In this report, we investigated the value of using all 77 breast cancer susceptibility loci identified to date for risk stratification. Previous studies of polygenic risk have assumed a log-additive model for combining SNPs; however, this assumption needs to be evaluated empirically. We first assessed whether interaction between SNP pairs could influence the joint contribution of genetic factors on disease risk by testing for all possible pair-wise interactions between SNPs. We then constructed polygenic risk scores (PRSs) to capture the combined effects of the 77 SNPs on overall breast cancer risk, as well as on the risk of ER-positive and ER-negative disease separately. We estimated absolute risks of developing breast cancer for different levels of the PRS, accounting for the competing risk of mortality from other causes. Effect sizes were confirmed in one large study (pKARMA) that was not part of any SNP discovery set. We discuss the degree of breast cancer risk stratification obtained in women with and without a family history of breast cancer.
Methods
Study Subjects and Genotyping
Study participants for the primary analyses (set 1) were 89 049 women of European origin participating in 41 studies in BCAC. All studies were approved by the relevant institutional review boards, and all individuals gave written informed consent. Samples were genotyped using a custom Illumina iSelect array (iCOGS) comprising 211 155 SNPs (
15). For some analyses, a further 72 014 women in BCAC genotyped for the relevant SNPs in earlier experiments were included (set 2). For PRS analyses (67 054 women), studies that oversampled breast cancer cases with a family history (21 995 women) were excluded.
Supplementary Tables 1–3(available online) show study designs and numbers of breast cancer cases and control women included.
Analyses were based primarily on variants reported to be associated (at
P< 5x10
-8) by COGS or previous publications, with either breast cancer overall or ER-negative disease. SNPs and regions included are summarized in
Supplementary Table 4 (available online).
Statistical Methods
Tests for pair-wise SNP*SNP interactions (departures from a multiplicative model) were carried out using logistic regression, with breast cancer as the outcome. The two SNPs were each coded as a categorical variable (ie, fitting a separate parameter for heterozygous and risk-allele homozygous genotypes), while the interaction term (SNP1*SNP2) was included as continuous covariate. All analyses were adjusted for study and seven principal components (PC) to account for population substructure (
15). Additional interaction tests used are described in the
Supplementary Methods (available online).
To investigate the association between breast cancer risk and the combined effects of 77 SNPs, a PRS was derived for each individual using the formula:
PRS=β1x1+β2x2+… βkxk…+βnxn
where
β k is the per-allele log odds ratio (OR) for breast cancer associated with the minor allele for SNP
k, and
x k the number of alleles for the same SNP (0, 1, or 2), and n = 77 is the total number of SNPs. Thus, the PRS summarizes the combined effect of the SNPs, ignoring departures from a multiplicative model (
18). SNPs and corresponding odds ratios used in derivation of PRSs are summarized in
Supplementary Table 4 (available online).
Logistic regression models were used to estimate the odds ratios for breast cancer by percentile of the PRS, with the middle quintile category (40th to 60th percentile) as the reference. Observed odds ratios for breast cancer by percentile of the PRS were compared with predicted odds ratios under a multiplicative polygenic model of inheritance. Modification of the PRS by age or by family history of breast cancer in a first-degree relative was evaluated by fitting additional interaction terms in the model. All tests of statistical significance were two-sided. The thresholds for statistical significance are indicated below.
The absolute risk of overall breast cancer, ER-positive and ER-negative breast cancer for individuals in each risk category, was calculated taking into account the competing risk of dying from other causes apart from breast cancer. Approximate confidence limits for the absolute risk were derived from the variance-covariance matrix of the log (relative risk) parameters in the logistic regression analysis. Detailed methods are provided in
Supplementary Methods (available online).
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