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Breast Cancer Res Treat. Author manuscript; available in PMC Nov 1, 2013.
Published in final edited form as:
PMCID: PMC3482828
NIHMSID: NIHMS410410
Evaluation of chromosome 6p22 as a breast cancer risk modifier locus in a follow-up study of BRCA2 mutation carriers
Kristen N. Stevens,1 Xianshu Wang,2 Zachary Fredericksen,1 Vernon S. Pankratz,1 Mark H. Greene,3 Irene L. Andrulis,4,5,6,7 Mads Thomassen,8 Maria Caligo,9 SWE-BRCA,10,11 Katherine L. Nathanson,12 Anna Jakubowska,13 Ana Osorio,14 Ute Hamann,15 Andrew K. Godwin,16 Dominique Stoppa-Lyonnet,17,18 Melissa Southey,19 Saundra S. Buys,20 Christian F. Singer,21 Thomas V.O. Hansen,22 Adalgeir Arason,23,24 Kenneth Offit,25 Marion Piedmonte,26 Marco Montagna,27 Evgeny Imyanitov,28 Laima Tihomirova,29 Lara Sucheston,30 Mary Beattie,31 HEBON,32 GC-HBOC,33 Susan L. Neuhausen,34 CONSIT Team,35 Csilla I. Szabo,36 kConFab,37 Jacques Simard,38 Amanda B. Spurdle,39,37 Sue Healey,39 Xiaoqing Chen,39 Timothy R. Rebbeck,40 Douglas F. Easton,41 Georgia Chenevix-Trench,39 Antonis C Antoniou,41 and Fergus J. Couch2
1Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA
2Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
3Clinical Genetics Branch, US National Cancer Institute, Rockville, Maryland, USA
4Ontario Cancer Genetics Network (OCGN), Cancer Care Ontario, Toronto, Ontario, Canada
5Fred A. Litwin Center for Cancer Genetics, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, New York, USA
6Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
7Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
8Odense University Hospital, Department of Clinical Genetics, Odense, Denmark
9Division of Surgical, Molecular and Ultrastructural Pathology, Department of Oncology, University of Pisa and Pisa University Hospital, Pisa, Italy
10SWE-BRCA collaborators: Per Karlsson, Margareta Nordling, Annika Bergman and Zakaria Einbeigi, Gothenburg, Sahlgrenska University Hospital; Marie Stenmark-Askmalm and Sigrun Liedgren, Linköping University Hospital; Åke Borg, Niklas Loman, Håkan Olsson, Maria Soller, Helena Jernström, Katja Harbst and Karin Henriksson, Lund University Hospital; Annika Lindblom, Brita Arver, Anna von Wachenfeldt, Annelie Liljegren, Gisela Barbany-Bustinza and Johanna Rantala, Stockholm, Karolinska University Hospital; Beatrice Melin, Henrik Grönberg, Eva-Lena Stattin and Monica Emanuelsson, Umeå University Hospital; Hans Ehrencrona, Richard Rosenquist and Niklas Dahl, Uppsala University Hospital.
11Swedish Breast Cancer Study, Sweden
12Abramson Cancer Center and Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
13International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
14Human Genetics Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Madrid, Spain and Spanish Network on Rare Diseases (CIBERER)
15Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany
16Women's Cancer Program, Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania
17INSERM U509, Service de Génétique Oncologique, Institut Curie, Université Paris-Descartes, Paris, France;
18GEMO study: Cancer Genetics Network “Groupe Génétique et Cancer”, Fédération Nationale des Centres de Lutte Contre le Cancer, France
19Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Australia
20Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA
21Department of Obstetrics and Gynecology and Comprehensive Cancer Center MUW, Medical University of Vienna, Vienna, Austria
22Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
23Department of Pathology, Landspitali-LSH, Reykjavik, Iceland
24Faculty of Medicine, University of Iceland, Reykjavik, Iceland
25Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA
26GOG Statistical and Data Center, Roswell Park Cancer Institute, Buffalo, New York, USA
27Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV - IRCCS, Padua, Italy
28Laboratory of Molecular Oncology, N.N. Petrov Institute of Oncology, St.-Petersburg, Russia
29Latvian Biomedical Research and Study Centre, Riga, Latvia
30Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York, USA
31Department of Medicine, University of California at San Francisco, San Francisco, California, USA
32HEreditary Breast and Ovarian Cancer Group Netherlands (HEBON)
33German Consortium for Hereditary Breast and Ovarian Cancer
34Department of Population Sciences, Beckman Research Institute of the City of Hope, Duarte, California, USA
35CONsorzio Studi ITaliani sui Tumori Ereditari Alla Mammella
36Department of Biological Sciences, University of Delaware, Newark, Delaware, USA
37Kathleen Cuningham Consortium for Research into Familial Breast Cancer—Peter MacCallum Cancer Center, Melbourne, Australia
38Canada Research Chair in Oncogenetics, Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec and Laval University
39Queensland Institute of Medical Research, Brisbane, Australia
40Northern Ireland Regional Genetics Center, Belfast City Hospital, Belfast, United Kingdom
41Center for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
Corresponding author: Fergus J. Couch, Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA, Phone: 507-284-3623, Fax: 507-538-1937, couch.fergus/at/mayo.edu
Several common germline variants identified through genome-wide association studies of breast cancer risk in the general population have recently been shown to be associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. When combined, these variants can identify marked differences in the absolute risk of developing breast cancer for mutation carriers, suggesting that additional modifier loci may further enhance individual risk assessment for BRCA1 and BRCA2 mutation carriers. Recently, a common variant on 6p22 (rs9393597) was found to be associated with increased breast cancer risk for BRCA2 mutation carriers [Hazard ratio (HR)=1.55, 95% CI 1.25–1.92, p=6.0×10−5]. This observation was based on data from GWAS studies in which, despite statistical correction for multiple comparisons, the possibility of false discovery remains a concern. Here we report on an analysis of this variant in an additional 6,165 BRCA1 and 3,900 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). In this replication analysis, rs9393597 was not associated with breast cancer risk for BRCA2 mutation carriers [HR=1.09, 95% CI 0.96–1.24, p=0.18]. No association with ovarian cancer risk for BRCA1 or BRCA2 mutation carriers or with breast cancer risk for BRCA1 mutation carriers was observed. This follow-up study suggests that, contrary to our initial report, this variant is not associated with breast cancer risk among individuals with germline BRCA2 mutations.
Keywords: BRCA1, BRCA2, genetic modifier, association study
Common genetic variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers and can be potentially used for risk modeling and assessment [18]. These variants include susceptibility alleles that achieved genome-wide significant associations (p < 5 × 10−8) with breast cancer in BRCA1 mutation carriers (19p13 rs8170, Ptrend=2.3 × 10−9) [1] and in BRCA2 mutation carriers (FGFR2 rs2981582, Ptrend=1.7 × 10−11) [2]. Variants in other known breast cancer risk loci such as TNRC9/TOX3 (rs3803662), MAP3K1 (rs889312), LSP1 (rs3817198), 2q35 (rs13387042), SLC4A7/NEK10 (rs4973768), 5p12 (rs10941679) and ZNF365 (rs16917302) have also been found to display moderately significant associations with breast cancer in BRCA2 mutation carriers [2, 46]. Similarly, variants in the TNRC9/TOX3 2q35, ESR1, and PTHLH loci have been moderately associated with risk for BRCA1 mutation carriers [5, 7, 8]. These findings suggest that the common genetic factors involved in susceptibility to breast cancer in the general population may also influence risk of breast cancer for BRCA1 and BRCA2 mutation carriers, although there appears to be little overlap in the breast cancer risk modifiers for women with BRCA1 and BRCA2 mutations. Furthermore, risk prediction models for BRCA2 mutation carriers incorporating common risk modifier loci suggest that the combined effects of these SNPs can distinguish marked differences in the absolute risk of developing breast cancer [5].
Based on the observation that common breast cancer susceptibility loci influence risk for BRCA1 and BRCA2 mutation carriers, we recently reported a study evaluating SNPs identified from two breast cancer genome-wide association studies (GWAS) and risk of breast cancer in BRCA1 (n=3,451) and BRCA2 (n=2,006) mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) [3]. We found an association between a locus at chromosome 6p22 (rs9393597) and risk of breast cancer in BRCA2 mutation carriers (Hazard ratio (HR)=1.55; 95% Confidence interval (CI) 1.25–1.92; p=6.0×10−5). Since that time, women from an additional 19 CIMBA study centers have been genotyped for this variant for a total 6,165 BRCA1 and 3,900 BRCA2 mutation carriers. Here, we further evaluate this SNP in this larger cohort of CIMBA BRCA1 and BRCA2 mutation carriers to attempt to replicate our findings in an independent cohort of women.
Subjects
Female carriers of deleterious mutations in BRCA1 and BRCA2 were identified through CIMBA. A total of 28 studies from 19 countries provided clinical data, risk factor data, and rs9393957 genotypes from BRCA1 and BRCA2 mutation carriers (Table 1, Supplementary Table 1). Eligibility for CIMBA participation was restricted to women with deleterious BRCA1 or BRCA2 mutations over age 18 years at the time of ascertainment [3]. Information was collected on year of birth, age at last follow up or bilateral prophylactic oophorectomy and/or mastectomy, age at breast and/or ovarian cancer diagnosis, mutation description and country of residence. Related individuals were attributed common family identifiers. All contributing studies received approvals from institutional review committees at their host institutions.
Table 1
Table 1
Summary characteristics for 10,065 eligible BRCA1 and BRCA2 carriers
SNP genotyping
DNA samples from 10 studies were genotyped for rs9393597 using the iPLEX Mass Array (Sequenom, San Diego, CA, USA). Another 21 studies genotyped samples using the 5’ endonuclease assay (TaqMan) (Applied Biosystems, Carlsbad, CA, USA) using reagents tested centrally. Genotyping centers included at least 2% duplicate samples and no template controls in every plate. Samples from affected and unaffected carriers were arranged randomly. All studies exhibited SNP call rates >95% and duplicate concordance >98%. To assess the accuracy of genotyping, a standard set of 95 Coriell DNA samples (HAPMAPP01) were genotyped by each genotyping center. All centers displayed >98% concordance for the Coriell samples. From the 12,128 BRCA1 and BRCA2 mutation carriers with genotyping data, 639 were excluded because of failure to meet eligibility criteria; missing follow-up information (n=15), overlapping samples between study groups (n=168), poor genotyping quality (n=421), discordant genotypes (n=13), mutation carrier in both BRCA1 and BRCA2 (n=22). A further 646 subjects were excluded due to non-European ethnicity. Further evaluation of the data identified one study with significant deviation from Hardy–Weinberg equilibrium (HWE) (p=1×10−6) for rs9393597 in BRCA1 carriers (n=879). All genotypes from this study were excluded, leaving 6,165 BRCA1 and 3,900 BRCA2 mutation carriers for analysis.
Statistical Analyses
Associations between rs9393597 and breast cancer risk for BRCA1 and BRCA2 mutation carriers were evaluated using a weighted Cox proportional hazards models [9]. For breast cancer analyses, each subject was followed from birth to the earliest event: breast cancer, bilateral mastectomy, ovarian cancer, last follow-up, or age 80 years. To adjust for the non-random sampling of mutation carriers with respect to disease phenotype, individuals were assigned weights based upon mutation status, breast cancer affected/unaffected status, and age at event or age at censoring [9], such that the weighted breast cancer incidence rates were consistent with established breast cancer risk estimates for BRCA1 and BRCA2 mutation carriers. For ovarian cancer analyses, separate disease-specific weights were applied and prophylactic oophorectomy replaced prophylactic mastectomy as a censoring variable [10]. All analyses were stratified by year of birth (based on quartiles of unaffected), ethnicity, and country of residence. A robust variance approach was used to estimate the standard errors of the parameters to allow for the dependence of individuals from the same family. Primary tests for association between rs9393597 and cancer risk were performed under a log-additive model. Hazard ratio estimates were obtained to summarize the relative risk of cancer for heterozygous and separately homozygous carriers of the minor allele of rs9393597. Heterogeneity among study sites was assessed by including a genotype by study interaction term in the model and testing for differences in the hazard ratios by study with a multiple degree-of-freedom test of significance. In sensitivity analyses, the data were analyzed while treating prophylactic oophorectomy as a time-dependent covariate and the influence of survival bias was explored by excluding subjects diagnosed with breast cancer more than five years prior to age at recruitment.
In total, 6,165 BRCA1 and 3,900 BRCA2 mutation carriers were eligible for the pooled analysis of associations between rs9393597 and risk of breast and ovarian cancer. Characteristics of the eligible mutation carriers, after quality control exclusions, are summarized in Table 1. In breast cancer analyses, 3,120 BRCA1 and 2,188 BRCA2 mutation carriers were followed until the first breast cancer diagnosis and 3,045 BRCA1 and 1,712 BRCA2 mutation carriers were followed until bilateral prophylactic mastectomy, ovarian cancer or age at last follow up. Among the 3,900 women with BRCA2 mutations, the minor (G) allele of rs9393597 was not significantly associated with breast cancer risk [HR=1.09, 95% CI 0.96–1.24, p=0.18] (Table 2). Consistent with our original report, there was no association between rs9393597 and risk of breast cancer among BRCA1 mutation carriers [HR=0.98, 95% CI 0.90 – 1.07, p=0.68] (Supplementary Table 2).
Table 2
Table 2
Associations between rs9393957 and risk of cancer in BRCA2 mutation carriers.
To evaluate the possibility of survival bias, we excluded all cases diagnosed with breast cancer more than five years before recruitment in the overall dataset (Table 2). The association between rs9393597 and breast cancer risk remained non-significant [HR=1.03, 95% CI 0.88–1.19, p=0.74]. To assess the influence of risk-reducing oophorectomy (RRO), which is known to reduce the risk of breast cancer in mutation carriers by as much as 50% [11], RRO was next included as a time-dependent covariate in the analysis. We did not observe a substantial change in the estimate of significance of the rs9393597 association with breast cancer [HR=1.07, 95% CI 0.94–1.23, p=0.27] (Table 2). Similar analyses showed no significant associations in BRCA1 mutation carriers (Supplementary Table 2). Since BRCA1 and BRCA2 mutations are also associated with increased risk of ovarian cancer, we next evaluated associations with ovarian cancer by following subjects until the first ovarian cancer diagnosis or until the earliest of bilateral prophylactic oophorectomy, breast cancer or age at last follow-up. No significant associations with ovarian cancer were observed for either BRCA1 HR=1.10, 95% CI 0.96–1.27, p=0.18] or BRCA2 HR=1.18, 95% CI 0.88–1.58, p=0.28] mutation carriers (Table 2, Supplementary Table 2).
The SNP rs9393597 in the LOC134997 locus on chromosome 6p22 has previously been shown to be associated with breast cancer risk for BRCA2 mutation carriers [HR=1.55, 95% CI 1.25–1.92, p=6×10−5] [3], although it has never been reported to be associated with breast cancer risk in the general population. Here we re-evaluated the association between rs9393597 and breast cancer in a total of 6,165 BRCA1 and 3,900 BRCA2 mutation carriers from 28 CIMBA study centers to replicate the association and to more accurately estimate the influence of the SNP on breast cancer risk. We found that the variant is not associated with breast cancer risk for either BRCA2 mutation carriers [HR=1.09, p=0.18] or BRCA1 mutation carriers [HR=0.98, p=0.68]. Additional analyses exploring potential sources of bias, such as the exclusion of prevalent cases and accounting for risk-reducing oophorectomies, did not substantially alter our results. Further, this locus was not associated with ovarian cancer risk for either BRCA1 or BRCA2 mutation carriers.
Compared to our original findings [3], we had a nearly two-fold increase in sample size for both women with BRCA1 (6,165 compared to 3,451 carriers) and BRCA2 (3,900 compared to 2,006 carriers) mutations. This suggests that the lack of association seen in the current study is unlikely to be due to inadequate power, even for modest rs9393597 effect sizes. This study also utilized subjects from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) as in the original report, such that genotyping and analyses were performed using the same robust quality control methods.
Variation in eight loci has been associated with modification of breast cancer risk for BRCA2 mutation carriers [22, 46], exhibiting effects ranging from HR=1.10 for MAP3K1 to HR=1.30 for FGFR2 . However, we show here that rs9393597 does not influence breast cancer risk for women with either BRCA1 or BRCA2 mutations, and should not be used in risk prediction modesl. CIMBA continues to enroll BRCA1 and BRCA2 mutation carriers, so that the association between rs9393597 and breast cancer risk may be re-evaluated in an even larger cohort of mutation carriers. However, given the current results we conclude that the 6p22 locus is not an important risk modifier for women with BRCA1 or BRCA2 mutations.
Supplementary Material
10549_2012_2255_MOESM1_ESM
Acknowledgements
This study by the Consortium of Investigators of Modifiers of BRCA1 /2 was supported by grants from Cancer Research UK and by National Institutes of Health grant CA128978, the Komen Foundation for the Cure and the Breast Cancer Research Foundation and by grants from Cancer Research UK (C12292/A11174 and C1287/A10118). All study-specific grants are below.
Cancer Research UK provided financial support for this work. A.C.A. is a Senior Cancer Research UK Cancer Research Fellow. D.F.E. is Cancer Research UK Principal Research Fellow. S.L.N., the Morris and Horowitz Families Endowed Professor, and Y.C.D. were supported by NIH CA74415.The MAGIC study is supported by NIH grants R01-CA083855 and R01-CA9677. City of Hope Clinical Cancer Genetics Community Network and the Hereditary Cancer Research Registry, supported in part by Award Number RC4CA153828 (PI: J.N. Weitzel) from the National Cancer Institute and the Office of the Director, National Institutes of Health. The Mayo Clinic study was supported in part by the Breast Cancer Research Foundation (BCRF), a grant from Susan G. Komen for the Cure, the Mayo Clinic Breast Cancer SPORE (P50-CA116201), and NIH grants CA122340 and CA128978 to F.J.C. KNS is a Mayo Cancer Genetic Epidemiology Training Program (CA92049-09) fellow. The Italian study (CONsorzio Studi Italiani Tumori Ereditari Alla Mammella, CONSIT TEAM) is funded in part by grants from Fondazione Italiana per la Ricerca sul Cancro (Special Project “Hereditary tumors”), Associazione Italiana per la Ricerca sul Cancro (8713), Italian Ministry of Health (Extraordinary National Cancer Program 2006 “Alleanza contro il Cancro”, and “Progetto Tumori Femminili”), Italian Ministry of Education, University and Research (Prin 2008) and by funds from Italian citizens who allocated the 5 × 1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects “5 × 1000”). CONSIT TEAM acknowledges Daniela Zaffaroni of the Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy;Bernardo Bonanni and Monica Barile of the Istituto Europeo di Oncologia, Milan, Italy; Riccardo Dolcetti of the Centro di Riferimento Oncologico, IRCCS, Aviano (PN), Italy; Liliana Varesco of the AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy; Laura Ottini of the University “La Sapienza”, Rome, Italy; Laura Papi of the University of Florence, Florence, Italy; and the personnel of the Cogentech, Cancer Genetic Test Laboratory, Milan, Italy. C.I.S. is supported by the Mayo Rochester Early Career Development Award for Non-Clinician Scientists. We acknowledge the contributions of Petr Pohlreich and Zdenek Kleibl (Department of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic) and the support of the Grant Agency of the Czech Republic, project No. GP301/08/P103 (to M.Z.). We acknowledge the contribution of Kim De Leeneer and Anne De Paepe. This research was supported by grant 1.5.150.07 from the Fund for Scientific Research Flanders (FWO) to Kathleen Claes and by grant 12051203 from the Ghent University to Anne De Paepe. Bruce Poppe is Senior Clinical Investigator of the Fund for Scientific Research of Flanders (FWO—Vlaanderen). Kim De Leeneer is supported by the Vlaamse Liga tegen Kanker through a grant of the Foundation Emmanuel van der Schueren. L.F., Machackova Eva, and Lukesova Miroslava's are supported through the Ministry of Health grant CR-MZ0 MOU 2005. The research of P.L. Mai and M.H. Greene was supported by the Intramural Research Program of the US National Cancer Institute, and by support services contracts NO2-CP-11019-50 and N02-CP-65504 with Westat, Inc, Rockville, MD. Genotyping of NCI DNA samples was performed by NCI's Core Genotyping Facility, Gaithersburg, MD. We thank the investigators of the Australia New Zealand Gynaecological Oncology Group (ANZGOG). Ontario Cancer Genetics Network (OCGN) thanks Mona Gill, Lucine Collins, Nalan Gokgoz, Teresa Selander, Nayana Weerasooriya, and members of the Ontario Cancer Genetics Network for their contributions to the study. The SMC study was supported in part by the Israel Cancer Association (ICA).SWE-BRCA acknowledge collaborators Per Karlsson, Margareta Nordling, Annika Bergman, and Zakaria Einbeigi, Gothenburg, Sahlgrenska University Hospital; Sigrun Liedgren, Linkoping University Hospital; Niklas Loman, Håkan Olsson, Ulf Kristoffersson, Helena Jernström, Katja Harbst, and Karin Henriksson, Lund University Hospital; Brita Arver, Anna von Wachenfeldt, Annelie Liljegren, and Gisela Barbany-Bustinza, Stockholm, Karolinska University Hospital; Henrik Grönberg, Eva-Lena Stattin, and Monica Emanuelsson, Umea University Hospital; Hans Ehrencrona, Richard Rosenquist Brandell, and Niklas Dahl, Uppsala University Hospital. University of Pennsylvania (UPENN) was supported by Breast Cancer Research Foundation (to K.L.N.); Cancer Genetics Network (to S.M.D.), Marjorie Cohen Foundation (to S.M.D.). IHCC was supported by Grant PBZ_KBN_122/P05/2004.Spanish National Cancer Center (CNIO) thanks R.M. Alonso, G Pita, and R.M. Milne for their assistance. This study was partially supported by Fundación Mutua Madrileña, Asociación Española Contra el Cáncer, and the Spanish Ministry of Science and Innovation (FIS PI08 1120). Funded in part by the Basque Foundation for Health Innovation and Research (BIOEF): BIO07/CA/006. The DKFZ study was supported by the DKFZ. Douglas F. Easton is the PI of the EMBRACE study and acknowledges collaborators: North of Scotland Regional Genetics Service, Aberdeen: Helen Gregory, Zosia Miedzybrodzka. West Midlands Regional Clinical Genetics Service, Birmingham: Carole McKeown, Laura Boyes. South West Regional Genetics Service, Bristol: Alan Donaldson. Medical Genetics Services for Wales, Cardiff: Alexandra Murray, Mark Rogers, Emma McCann. St James's Hospital, Dublin & National Center for Medical Genetics, Dublin: David Barton. Peninsula Clinical Genetics Service. Exeter: Carole Brewer, Emma Kivuva, Anne Searle, Selina Goodman. West of Scotland Regional Genetics Service, Glasgow: Victoria Murday, Nicola Bradshaw, Lesley Snadden, Mark Longmuir, Catherine Watt, Sarah Gibson. South East Thames Regional Genetics Service, Guys Hospital London: Louise Izatt, Chris Jacobs, Caroline Langman. Leicestershire Clinical Genetics Service, Leicester: Julian Barwell. Yorkshire Regional Genetics Service, Leeds: Carol Chu, Tim Bishop, Julie Miller. Merseyside & Cheshire Clinical Genetics Service, Liverpool: Ian Ellis. Manchester Regional Genetics Service, Manchester: Felicity Holt. North East Thames Regional Genetics Service, NE Thames: Alison Male, Lucy Side, Anne Robinson. Nottingham Center for Medical Genetics, Nottingham: Carol Gardiner. Northern Clinical Genetics Service, Newcastle: Fiona Douglas, Oonagh Claber. Oxford Regional Genetics Service, Oxford: Diane McLeod, Dorothy Halliday, Sarah Durrell, Barbara Stayner. The Institute of Cancer Research and Royal Marsden NHS Foundation Trust: Ros Eeles, Susan Shanley, Nazneen Rahman, Richard Houlston, Elizabeth Bancroft, Lucia D'Mello, Elizabeth Page, Audrey Ardern-Jones, Kelly Kohut, Jennifer Wiggins, Elena Castro, Lisa Robertson. North Trent Clinical Genetics Service, Sheffield: Oliver Quarrell, Cathryn Bardsley. South West Thames Regional Genetics Service, London: Sheila Goff, Glen Brice, Lizzie Winchester. Wessex Clinical Genetics Service. Princess Anne Hospital, Southampton: Diana Eccles, Anneke Lucassen, Gillian Crawford, Emma Tyler, Donna McBride. D.F.E., S.P., M.C., D.F. and C.O. are funded by Cancer Research-UK Grants C1287/A10118 and C1287/A8874. D.C. is supported by Cancer Research-UK Grant C8197/A10123. HEBON stands for The Hereditary Breast and Ovarian Cancer Research Group Netherlands and consists of the following Collaborating Centers: Coordinating center: Netherlands Cancer Institute, Amsterdam, NL: M.A. Rookus, F.B.L. Hogervorst, F.E. van Leeuwen, S. Verhoef, M.K. Schmidt, J.L. de Lange; Erasmus Medical Center, Rotterdam, NL: J.M. Collée, A.M.W. van den Ouweland, M.J. Hooning, C. Seynaeve, C.H.M. van Deurzen; Leiden University Medical Center, NL: C.J. van Asperen, J.T. Wijnen, R.A. Tollenaar, P. Devilee, T.C.T.E.F. van Cronenburg; Radboud University Nijmegen Medical Center, NL: C.M. Kets, A.R. Mensenkamp; University Medical Center Utrecht, NL: M.G.E.M. Ausems, R.B. van der Luijt; Amsterdam Medical Center, NL: C.M. Aalfs, T.A.M. van Os; VU University Medical Center, Amsterdam, NL: J.J.P. Gille, Q. Waisfisz, H.E.J. Meijers- Heijboer; University Hospital Maastricht, NL: E.B. Gómez-Garcia, M.J. Blok; University Medical Center Groningen, NL: J.C. Oosterwijk, A.H. van der Hout, M.J. Mourits, G.H. de Bock. The Netherlands Foundation for the detection of hereditary tumours, Leiden, NL: H.F. Vasen. The HEBON study is supported by the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, the NWO grant 91109024, the Pink Ribbon grant 110005 and the BBMRI grant CP46/NWO. The Breast Cancer Family Registry (BCFR) was supported by the National Cancer Institute, National Institutes of Health under RFA-CA-06-503 and through cooperative agreements with members of the BCFR and Principal Investigators, including Cancer Care Ontario (U01 CA69467), Cancer Prevention Institute of California (U01 CA69417), Columbia University (U01 CA69398), Fox Chase Cancer Center (U01 CA69631), Huntsman Cancer Institute (U01 CA69446), University of Melbourne (U01 CA69638), and Research Triangle Institute Informatics Support Center (RFP No. N02PC45022-46). Samples from the CPIC, FCCC, HCI, and were processed and distributed by the Coriell Institute for Medical Research. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the BCFR, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government or the BCFR. The GEMO study is supported by the Ligue National Contre le Cancer, Association for International Cancer Research Grant AICR-07-0454, and the Association “Le cancer du sein, parlons-en!” Award. We wish to thank all the GEMO collaborating groups for their contribution to this study. GEMO Collaborating Centers are: Coordinating Centres, Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Hospitalier Universitaire de Lyon/Centre Léon Bérard, and UMR5201 CNRS, Université de Lyon, Lyon: Laure Barjhoux, Sophie Giraud, Mélanie Léone, Sylvie; and INSERM U509, Service de Génétique Oncologique, Institut Curie, Paris: Marion Gauthier-Villars, Claude Houdayer, Virginie Moncoutier, Muriel Belotti. Institut Gustave Roussy, Villejuif: Brigitte Bressac-de-Paillerets, Audrey Remenieras, Véronique Byrde, Olivier Caron, Gilbert Lenoir. Centre Jean Perrin, Clermont-Ferrand: Yves- Jean Bignon, Nancy Uhrhammer. Institut Paoli Calmettes, Marseille: Violaine Bourdon, François Eisinger. Groupe Hospitalier Pitié-Salpétrière, Paris: Florence Coulet, Chrystelle Colas, Florent Soubrier. CHU de Arnaud-de-Villeneuve, Montpellier: Isabelle Coupier. Centre Oscar Lambret, Lille: Jean-Philippe Peyrat, Joëlle Fournier, Françoise Révillion, Philippe Vennin, Claude Adenis. Centre René Huguenin, St Cloud: Etienne Rouleau, Rosette Lidereau, Liliane Demange. Centre Paul Strauss, Strasbourg: Danièle Muller, Jean-Pierre Fricker. Institut Bergonié, Bordeaux: Michel Longy, Nicolas Sevenet. Institut Claudius Regaud, Toulouse: Christine Toulas, Rosine Guimbaud, Laurence Gladieff, Viviane Feillel. CHU de Grenoble: Christine Rebischung. CHU de Dijon: Cécile Cassini. CHU de St-Etienne: Fabienne Prieur. Hôtel Dieu Centre Hospitalier, Chambéry: Sandra Fert Ferrer. CBCS thanks Mette K. Andersen and Susanne Kjaergaard for clinical data. The work was supported by the Neye Foundation. GOG was supported by National Cancer Institute grants of the Gynecologic Oncology Group Administrative Office (CA 27469), the GOG Tissue Bank (CA 27469), and the Gynecologic Oncology Group Statistical and Data Center (CA 37517 and CA 101165). GOG's participation was supported through funding provided by both intramural (Clinical Genetics Branch, DCEG) and extramural (Community Oncology and Prevention Trials Program—COPTRG) NCI programs. Genotyping of GOG DNA samples was performed by NCI's Core Genotyping Facility. The technical expertise of Tim Sheehy and Amy Hutchinson is gratefully acknowledged. OSU CCG was funded by the OSU Comprehensive Cancer Center. We thank Kevin Sweet and Caroline Craven for patient accrual and data management, the Human Genetics Sample Bank for sample preparation, and the OSU Nucleic Acids Shared Resource for plate reads. IOVHBOCS was supported by the Ministero dell'Università e della Ricerca, Ministero della Salute, and Alleanza Contro il Cancro.N.N. Petrov Institute of Oncology (NNPIO) was supported by the Russian Foundation for Basic Research (grants 08-04-00369-a, 09-04-90402, and 10-04-92110-a), the Commission of the European Communities (grant PITN-GA-2009- 238132), and through a Royal Society International Joint grant (JP090615). BFBOCC was supported by Latvian Science Council grant Nr.10.0010.08. BFBOCC also acknowledges the Genome Database of Latvian Population, Latvian Biomedical Research and Study Centre for providing data and DNA samples for BFBOCC (L.V.), and Ramunas Janavicius (Vilnius 20 University Hospital Santariskiu Clinics, Lithuania) for data and DNA samples for BFBOCC (L.T.). UKFOCR was supported by a project grant from CRUK to Paul Pharoah. We thank Carole Pye and Patricia Harrington for family recruitment and technical support. We would like to acknowledge the Roswell Park Alliance Foundation for their continued support of the Gilda Radner Ovarian Family Cancer Registry. GRFOCR qould like to acknowledge Kirsten Moysich (Department of Cancer Prevention and Control) and Kunle Odunsi (Departments Gynecologic Oncology and Immunology). WCRI was supported by the American Cancer Society Early Detection Professorship and Entertainment Industry Foundation. GC-HBOC is supported by a grant of the German Cancer Aid (grant 107054). We thank Juliane Köhler for her excellent technical assistance, Ellen Kirsch, Isabell Eisenhauer, Hans-Jörg Plendl, Thomas Neumann, Ulrike Siebers-Rehnelt, Doris Steinemann, Britta Skawran, Patricia Steiner, and the 12 centers of the GC-HBOC for providing samples and clinical data. HEBCS thanks Tuomas Heikkinen and Dr. Carl Blomqvist for their help with the patient data and samples. The HEBCS study has been financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (132473), the Finnish Cancer Society, and the Sigrid Juselius Foundation. Trinidad Caldes and Miguel de la Hoya were supported by FIS 09/00859 and RD06/0020/0021 (RTICC; ISCIII) Spanish Ministry of Science and Innovation. Dumont, Martine Tranchant for sample management and skillful technical assistance. Jacques Simard- J.S. is Chairholder of the Canada Research Chair in Oncogenetics. This work was supported by the Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program and by the Canadian Breast Cancer Research Alliance-grant #019511. kConFab thanks Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the Clinical Follow Up Study (funded by NHMRC grants 145684, 288704, and 454508 and currently by the National Breast Cancer Foundation and Cancer Australia #628333) for their contributions to this resource, and the many families who contribute to kConFab. kConFab is supported by grants from the National Breast Cancer Foundation, the National Health and Medical Research Council (NHMRC), and by the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia, and the Cancer Foundation of Western Australia, Amanda Spurdle is supported by an NHMRC Senior Research Fellowship, and Georgia Chenevix-Trench by an NHMRC Senior Principal Research Fellowship. ILUH was funded by the Landspitali University Hospital Research Fund and by the Icelandic association: “Walking for Breast Cancer Research”. MSKCC acknowledges support of the Sandra Taub Research Fund of the BCRF.
Footnotes
32 Co-first authors
Conflict of Interest
The authors declare that they have no conflict of interest.
1. Antoniou AC, Wang X, Fredericksen ZS, McGuffog L, Tarrell R, Sinilnikova OM, Healey S, Morrison J, Kartsonaki C, Lesnick T, et al. A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptornegative breast cancer in the general population. Nat Genet. 2010;42(10):885–892. [PMC free article] [PubMed]
2. Gaudet MM, Kirchhoff T, Green T, Vijai J, Korn JM, Guiducci C, Segre AV, McGee K, McGuffog L, Kartsonaki C, et al. Common genetic variants and modification of penetrance of BRCA2-associated breast cancer. PLoS Genet. 2010;6(10):e1001183. [PMC free article] [PubMed]
3. Wang X, Pankratz VS, Fredericksen Z, Tarrell R, Karaus M, McGuffog L, Pharaoh PD, Ponder BA, Dunning AM, Peock S, et al. Common variants associated with breast cancer in genome-wide association studies are modifiers of breast cancer risk in BRCA1 and BRCA2 mutation carriers. Hum Mol Genet. 2010;19(14):2886–2897. [PMC free article] [PubMed]
4. Antoniou AC, Sinilnikova OM, McGuffog L, Healey S, Nevanlinna H, Heikkinen T, Simard J, Spurdle AB, Beesley J, Chen X, et al. Common variants in LSP1, 2q35 and 8q24 and breast cancer risk for BRCA1 and BRCA2 mutation carriers. Hum Mol Genet. 2009;18(22):4442–4456. [PMC free article] [PubMed]
5. Antoniou AC, Beesley J, McGuffog L, Sinilnikova OM, Healey S, Neuhausen SL, Ding YC, Rebbeck TR, Weitzel JN, Lynch HT, et al. Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction. Cancer Res. 2010;70(23):9742–9754. [PMC free article] [PubMed]
6. Antoniou AC, Spurdle AB, Sinilnikova OM, Healey S, Pooley KA, Schmutzler RK, Versmold B, Engel C, Meindl A, Arnold N, et al. Common breast cancerpredisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers. Am J Hum Genet. 2008;82(4):937–948. [PubMed]
7. Antoniou AC, Kartsonaki C, Sinilnikova OM, Soucy P, McGuffog L, Healey S, Lee A, Peterlongo P, Manoukian S, Peissel B, et al. Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers. Hum Mol Genet. 2011;20(16):3304–3321. [PMC free article] [PubMed]
8. Antoniou AC, Kuchenbaecker KB, Soucy P, Beesley J, Chen X, McGuffog L, Lee A, Barrowdale D, Healey S, Sinilnikova OM, et al. Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. Breast Cancer Res. 2012;14(1):R33. [PMC free article] [PubMed]
9. Antoniou AC, Goldgar DE, Andrieu N, Chang-Claude J, Brohet R, Rookus MA, Easton DF. A weighted cohort approach for analysing factors modifying disease risks in carriers of high-risk susceptibility genes. Genet Epidemiol. 2005;29(1):1–11. [PubMed]
10. Antoniou AC, Rookus M, Andrieu N, Brohet R, Chang-Claude J, Peock S, Cook M, Evans DG, Eeles R, Nogues C, et al. Reproductive and hormonal factors, and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers: results from the International BRCA1/2 Carrier Cohort Study. Cancer Epidemiol Biomarkers Prev. 2009;18(2):601–610. [PubMed]
11. Rebbeck TR, Lynch HT, Neuhausen SL, Narod SA, Van't Veer L, Garber JE, Evans G, Isaacs C, Daly MB, Matloff E, et al. Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med. 2002;346(21):1616–1622. [PubMed]