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Breast Cancer Res Treat. Author manuscript; available in PMC 2011 June 1.
Published in final edited form as:
PMCID: PMC3077711
NIHMSID: NIHMS286212

The Leu33Pro polymorphism in the ITGB3 gene does not modify BRCA1/2-associated breast or ovarian cancer risks: results from a multicenter study among 15,542 BRCA1 and BRCA2 mutation carriers

Abstract

Integrins containing the β3 subunit are key players in tumor growth and metastasis. A functional Leu33Pro polymorphism (rs5918) in the β3 subunit of the integrin gene (ITGB3) has previously been suggested to act as a modifier of ovarian cancer risk in Polish BRCA1 mutation carriers. To investigate the association further, we genotyped 9,998 BRCA1 and 5,544 BRCA2 mutation carriers from 34 studies from the Consortium of Investigators of Modifiers of BRCA1/2 for the ITGB3 Leu33Pro polymorphism. Data were analysed within a Cox-proportional hazards framework using a retrospective likelihood approach. There was marginal evidence that the ITGB3 polymorphism was associated with an increased risk of ovarian cancer for BRCA1 mutation carriers (per-allele Hazard Ratio (HR) 1.11, 95% CI 1.00–1.23, p-trend 0.05). However, when the original Polish study was excluded from the analysis, the polymorphism was no longer significantly associated with ovarian cancer risk (HR 1.07, 95% CI 0.96–1.19, p-trend 0.25). There was no evidence of an association with ovarian cancer risk for BRCA2 mutation carriers (HR 1.09, 95% CI 0.89–1.32). The polymorphism was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers. The ITGB3 Leu33Pro polymorphism does not modify breast or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers.

Keywords: ITGB3 Leu33Pro, BRCA1, BRCA2, Breast cancer, Ovarian cancer

Introduction

Women harbouring deleterious germline mutations in the BRCA1 or BRCA2 gene face high life-time risks of developing breast and ovarian cancers [1-4]. Recent estimates of breast cancer risk by the age of 70 years range from 47% [5] to 87% [6] for BRCA1 mutation carriers and from 45% [7] to 84% [2] for BRCA2 mutation carriers. The corresponding risk of ovarian cancer was estimated to range from 15% [8] to 68% [9] for BRCA1 mutation carriers and 4.5% [8] to 31% [9] for BRCA2 mutation carriers. Penetrance estimates vary by family ascertainment criteria and also between and within families, suggesting that other genetic or environmental factors modify the disease risks [10, 11].

Integrins comprise a large family of cell surface receptors which control cell attachment to the extracellular matrix (ECM). They play a role in mammary gland biology with expression in all cell types within the gland [12] and activate intracellular signaling pathways that control proliferation, differentiation, apoptosis, cell motility, migration and survival [13, 14]. Integrins consist of noncovalently linked α and β subunits. In mammals, combinations of 18α and 8β subunits form at least 25 different proteins that bind specific ECM components [14, 15]. Two integrins containing the β3 subunit, αvβ3 and αIIbβ3, are key players in tumor growth and metastasis. Increased expression of these integrins in melanomas, gliomas, ovarian and breast cancers correlates with invasive tumor properties [16-20], whereas their inhibition reduces tumor growth and metastasis through disruption of tumor angiogenesis [21, 22].

The β3 integrin gene (ITGB3) is a plausible candidate for breast and ovarian cancer susceptibility. A previously reported single nucleotide polymorphism (SNP) rs5918, a nucleotide substitution of T to C at codon 33 in the mature protein, causes a leucine to proline exchange [23]. This variant introduces a nick in the polypeptide chain just N-terminal of the hybrid domain of β3, which is involved in dimerization with the αv and αIIb subunits during the formation of αvβ3 and αIIbβ3 integrins. It has been shown that ITGB3 Leu33Pro polymorphism is of functional significance in that it increases the interactions with fibrinogen [24, 25], results in an abnormal response to stimulation with thromboxane [26] and other agonists [27], enhances aggregation of platelets and generation of thrombins [28-30], decreases bleeding time [31], increases signaling through ERK2 of the MAPK [32] pathway and enhances cell migration [33].

A number of epidemiological studies have suggested associations of the ITGB3 Leu33Pro with the risk of developing cancers including non-Hodgkin lymphoma [34], colon [34], kidney [35], breast [36-41] and ovarian cancer [36, 42, 43]. However, little data exist on the influence of this polymorphism on breast and ovarian cancer risk for women with BRCA1 or BRCA2 mutations. A recent study conducted of Polish BRCA1 mutation carriers including 319 breast cancer cases, 146 ovarian cancer cases and 290 unaffected controls reported a significantly increased risk of ovarian cancer among carriers of the ITGB3 33Pro allele (ORadj 2.51, 95% CI 1.30–4.84, P = 0.006) [44]. In order to verify this original finding and to estimate the possible association of ITGB3 Leu33Pro with BRCA2 related cancer risk, we genotyped this polymorphism using a large series of BRCA1 and BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).

Materials and methods

Study sample

Eligible study subjects were women who carried a deleterious germline mutation in BRCA1 or BRCA2 and were 18 years old or older. Information on study subjects was submitted from 34 centers participating in CIMBA. Data collected included year of birth, mutation description, family membership, ethnicity, country of residence, age at last follow-up, ages at breast and ovarian cancer diagnosis and information on bilateral prophylactic mastectomy and oophorectomy. Only carriers of pathogenic BRCA1 or BRCA2 mutations were included in the study. These were mutations generating a premature termination codon (frameshifts, small deletions and insertions, nonsense mutations, splice site mutations, large genomic rearrangements), large in-frame deletions that spanned one or more exons, deletions of transcription regulatory regions (promoter and/or first exons) expected to cause lack of expression of mutant allele and missense variants classified as pathogenic by Breast Cancer Information Core (BIC) or using the algorithms of Goldgar et al. [45] and Chenevix-Trench et al. [46]. Truncating variants in exon 27 of BRCA2 were excluded.

All carriers participated in clinical and research studies at the host institutions under ethically approved protocols. Further details of the CIMBA initiative can be found elsewhere [47].

Women who were self-reported as “non-white” and those who carried pathogenic mutations in both BRCA1 and BRCA2 were excluded from the analysis. Possible overlaps between studies were investigated by comparing the year of birth, mutation description, and the reported ages to identify duplicate individuals. Where possible, additional CIMBA genotyping data were used to ensure that duplicated individuals were only included once in the analysis.

Genotyping

Twenty-one centers genotyped the ITGB3 Leu33Pro using a 5′ nuclease assay (TaqMan). PCR primers (5′-TCTCTTTGGGCTCCTGTCTTACA-3′ (forward) and 5′-GCAGATTCTCCTTCAGGTCACA-3′ (reverse) and probes (VIC-5′-TGAGCCCGGAGGCA-3′ and FAM-5′-TGAGCCCAGAGGCA-3′) were distributed centrally to each center. DNA samples from 11 centers were genotyped at the Queensland Institute of Medical Research, Brisbane, Australia, using iPLEX technology. PCR primers were 5′-ACGTTGGATGGCACAGTTATCCTTCAGCAG-3′ (forward) and 5′-ACGTTGGATGTCTTTGGGCTCCTGTCTTAC-3′ (reverse); the extension primer was 5′-AGCGAGGTGAGCCC-3′. One study performed genotyping by direct DNA sequencing on an ABI 3130XL Genetic Analyzer. PCR primers were 5′-GCTATTGGGAAGTGGTAGGGC-3′ (forward) and 5′-TGTCTCCAGAGCCCTTGTCG-3′ (reverse). IHCC geno-typed by PCR-based restriction fragment length polymorphism (RFLP) analysis as previously described [44].

In addition to the genotypes of patients, each study also provided genotypes for at least 2% of samples in duplicate, genotypes for a standard test plate containing 94 samples from the Coriell Cell Repository (New Jersey, USA), and cluster plots from Taqman analyses. Genotyping data were included in the analysis when they met the quality control criteria including an overall call rate of >95%, duplicate concordance and concordance of test plate genotypes of >98%. Samples that failed genotyping for two or more of genotyped SNPs at this CIMBA genotyping round (or ≥20% if typed using a multiplex platform) were also excluded. All studies passed these quality criteria. As an additional genotyping quality criterion we also assessed Hardy–Weinberg Equilibrium (HWE) for unrelated mutation carriers for each study separately. There was no significant evidence of deviation from HWE for any of the studies and all the studies were therefore included in the analysis.

Statistical analysis

The aim of the analysis was to evaluate the association between the ITGB3 Leu33Pro and risks of breast or ovarian cancer in BRCA1 and BRCA2 carriers. Women were classified according to their age of cancer diagnosis or their age at last observation. Three types of analysis were carried out. To evaluate the association with breast cancer risk, carriers were censored at the age of the first of the following events: breast cancer diagnosis (8,274 carriers), ovarian cancer diagnosis (1,507 carriers), bilateral prophylactic mastectomy (413 carriers) or age at last observation (5,348 carriers). Only those censored at a breast cancer diagnosis were assumed to be affected. To evaluate the association with ovarian cancer risk, carriers were censored at the age of ovarian cancer diagnosis (2,159 carriers), bilateral prophylactic oophorectomy (1,096) or age at last observation (12,287 carriers) whichever occurred first. Only those censored at ovarian cancer were assumed to be affected for the analysis. We did not censor at a breast cancer diagnosis in order to maximize the number of ovarian cancer cases used in the analysis. To evaluate whether our results were influenced by the fact we did not censor at breast cancer diagnosis, we also performed an analysis where individuals were censored at the first cancer diagnosis (breast or ovarian). In this we assumed that an individual was at risk of developing either breast or ovarian cancer.

Since BRCA1 and BRCA2 mutation carriers are not randomly sampled with respect to their disease status, standard methods of analysis can lead to biased estimates of the hazard ratios (HR) [46]. We therefore analyzed the data within a retrospective likelihood framework by modeling the likelihood of the observed genotypes conditional on the disease phenotypes. This approach is described in detail elsewhere [48]. Under this approach, the cancer incidence was assumed to depend on the underlying incidence through a Cox-proportional hazards model λi(t) = λ0(t) exp(βi), where exp(βi) is the hazard ratio for genotype i and λ0(t) is the cancer incidence rate in the baseline category. The baseline age-specific incidence rates in the Cox proportional-hazards model were chosen such that the overall cancer incidence rates, averaged over all genotypic categories, agree with external estimates of incidence for BRCA1 and BRCA2 mutation carriers [11]. The effect of each SNP was modelled either as a per-allele HR (multiplicative model) or as separate HRs for heterozygotes and homozygotes, and these were estimated on the log scale (i.e. βi). This analysis was performed separately for breast and ovarian cancer to evaluate the associations with each disease. In a further sensitivity analysis of the association with ovarian cancer risk, we extended the retrospective likelihood to allow for the fact that each mutation carrier is at risk of developing either breast or ovarian cancer. For this purpose we assumed that conditional on the genotype, the age-specific probability of developing ovarian cancer is independent of the probability of developing breast cancer. In this competing risk analysis, since the aim was to evaluate the association with ovarian cancer risk, we assumed that the SNP was not associated with the risk of developing breast cancer. Analyses were carried out with the pedigree-analysis software MENDEL [49]. We examined between-study heterogeneity by comparing the models that allowed for study-specific log-hazard ratios against models in which the same log-hazard ratio was assumed to apply to all studies. All analyses were stratified by study group and country of residence and used calendar-year- and cohort-specific breast cancer incidence rates for BRCA1 and BRCA2 mutation carriers [11].

To investigate whether SNP associations differed by mutation type, mutations were classified according to their predicted functional effect. Class 1 mutations include loss of function mutations caused by reduced transcript and protein levels due to nonsense-mediated decay (NMD) and/or degradation or instability of truncated proteins [50-52], translation re-initiation but no production of stable protein [53], or the absence of expression caused by deletion of transcription regulatory regions. Class 2 mutations comprise mutations expected to generate stable mutant proteins: missense mutations, in-frame deletions/insertions and truncating mutations with premature stop codons occurring in the last exon and thus not triggering NMD. Mutations whose consequences at transcript or protein level could not be inferred were not considered for this classification.

Results

In this study, we investigated the effect of the ITGB3 Leu33Pro on breast and ovarian cancer risk in female BRCA1 and BRCA2 mutation carriers from 34 centers participating in CIMBA. A total of 15,542 mutation carriers were eligible for inclusion in the analysis (9,998 BRCA1 and 5,544 BRCA2, Table 1). The genotype frequencies and estimated HRs by mutation and disease status are shown in Table 2. There was no evidence of association between breast cancer risk and the ITGB3 Leu33Pro for either BRCA1 or BRCA2 mutation carriers (per-allele HR 1.02, 95% CI 0.94–1.09 and 1.01, 95% CI 0.92–1.12 for BRCA1 and BRCA2, respectively). There was no evidence of heterogeneity in the HRs across studies (p-het = 0.38 and 0.41 for BRCA1 and BRCA2, respectively).

Table 1
Number of eligible BRCA1 and BRCA2 carriers by study group
Table 2
ITGB3 Leu33Pro (T>C, rs5918) genotype frequencies by disease status and hazard ratio estimates

There was marginal evidence of association with ovarian cancer risk for BRCA1 mutation carriers (per-allele HR 1.11, 95% CI 1.00–1.23, p-trend = 0.05) and there was no evidence of heterogeneity in the HRs across studies for BRCA1 mutation carriers (p-het = 0.13). However, when the IHCC study, where the original association was found, was excluded there was no evidence of association (HR 1.07, 95% CI 0.96–1.19, p-trend = 0.25). ITGB3 Leu33Pro was also not associated with ovarian cancer risk for BRCA2 mutation carriers (perallele HR 1.09, 95% CI 0.89–1.32). In assessing between-study heterogeneity for BRCA2 mutation carriers, study-specific log-hazard ratios converged to boundary conditions due to small numbers and it was not therefore possible to formally assess heterogeneity in the HRs between studies for BRCA2. To investigate whether ignoring breast cancer diagnoses influenced our results, we also analysed the data in a competing risks analysis framework and allowed individuals to be at risk of developing either breast or ovarian cancer. The HR estimates under this analysis were similar to the analysis which did not censor at a breast cancer diagnosis (Table 2).

Among BRCA1 mutation carriers, 6,716 carried class 1 mutations (frameshifts—72%, nonsense mutations—21%, splice site mutations—4% and large deletions or duplications—3%) and 2,678 class 2 mutations (frameshifts—60%, missense mutations—26%, nonsense mutations—5%, splice site mutations—2% and large deletions or duplications—7%). To investigate whether our results differ by mutation type, we carried out separate analyses for BRCA1 class 1 and class 2 mutations (Table 3). ITGB3 Leu33Pro was not associated with either breast or ovarian cancer risk for class 1 mutation carriers. In addition, there was no evidence of an association with breast cancer risk for BRCA1 class 2 mutations. However, there was evidence that the polymorphism is associated with ovarian cancer risk in BRCA1 class 2 mutation carriers (per-allele HR 1.24 95% CI 1.00–1.53, p-trend = 0.048). Since the original study (IHCC), where an association was reported [44], consists predominantly of class 2 mutations (~94% of all BRCA1 mutations in IHCC), we repeated the analysis by excluding the IHCC study and found no evidence of an association (HR 1.01, 95% CI 0.78–1.32, p-trend = 0.92).

Table 3
ITGB3 Leu33Pro (T>C, rs5918) genotype frequencies by disease status and ovarian cancer hazard ratio estimates for BRCA1 mutation carriers by mutation class

Discussion

We genotyped of 9,998 BRCA1 and 5,544 BRCA2 mutation carriers to investigate the hypothesis that the ITGB3 Leu33Pro polymorphism is associated with breast or ovarian cancer risk in BRCA1 or BRCA2 mutation carries. To our knowledge this is the largest study of its kind. Results from a smaller study had previously suggested that this polymorphism is associated with the risk of ovarian cancer in BRCA1 mutation carriers [44]. However, our results suggest that ITGB3 Leu33Pro is not associated with the risk of breast or ovarian cancer risk for BRCA1 or BRCA2 carriers. There was a marginal evidence of association with ovarian cancer risk for BRCA1 mutation carriers, but when the original study, where the association was reported, was excluded, there was no evidence of an association.

Several studies have investigated the associations between ITGB3 Leu33Pro with breast and ovarian cancer in the general population, but the results have been inconsistent [36-43]. One study reported an association between the homozygous 33Leu genotype and breast cancer risk [38], other studies suggested that the 33Pro allele is associated with breast cancer risk [36, 37, 39], and others reported no associations [40, 41]. An association of ITGB3 Leu33Pro was reported with ovarian cancer in the general population [43], but this was not confirmed in any other study [42]. In the latest and largest up to now study of 1,819 ovarian cancer patients, including 837 serous and 734 non-serous cases, and 2,353 controls performed by the Ovarian Cancer Association Consortium (OCAC) as part of a genome-wide association study [54], no significant association of ITGB3 Leu33Pro with overall ovarian cancer risk was found (per-minor allele OR 0.99, 95% CI 0.88–1.12, p-trend = 0.95). Furthermore, no associations were found when patients were subdivided by histologic subtype: serous (OR 0.94, 95% CI 0.80–1.09) and non-serous (OR 1.08, 95% CI 0.92–1.27) tumors (personal communication, Honglin Song). Since the majority of the BRCA1 mutation ovarian cancer tumors are serous [8], the absence of an association with ovarian cancer risk for BRCA1 mutation carriers is consistent with the lack of association for serous tumors in the general population.

Acknowledgements

Other contributing members of the CIMBA, the Consortium of Investigators of Modifiers of BRCA1/2-Related Cancer:

kConFab: Georgia Chenevix-Trench, Amanda B. Spurdle, Sue Healey, Xiaoqin Chen, Jonathan Beesley and kConFab Investigators; UCI: Susan L. Neuhausen, Yuan Chun Ding; MAYO: Fergus J. Couch, Xianshu Wang, Mary Karaus; MBCSG: Paolo Peterlongo, Siranoush Manoukian, Bernard Peissel, Bernardo Bonanni, Alessandra Viel, Paolo Radice; ModSQuaD: Csilla I. Szabo, Lenka Foretova, Michal Zikan, Bruce Poppe; NCI: Phuong L. Mai, Mark H. Greene; NICCC: Flavio Lejbkowicz, Gad Rennert; OCGN: Irene L. Andrulis, Hilmi Ozcelik, Gord Glendon; OUH: Mads Thomassen, Anne-Marie Gerdes, Torben A. Kruse; PBCS: Maria Adelaide Caligo, Grazia Lombardi; SMC: Yael Laitman, Bella Kaufman, Roni Milgrom, Shimrit Cohen, Ruth Gershoni-Baruch, Efrat Dragan, Eitan Friedman; SWE-BRCA: Niklas Loman, Per Karlsson, Hans Ehrencrona, Anna von Wachenfeldt; UPENN: Kurt D’Andrea, Susan M. Domchek, Katherine L. Nathanson, Timothy R. Rebbeck; IHCC: Pablo Serrano, Cezary Cybulski, Tadeusz Debniak, Bohdan Górski, Tomasz Byrski, Tomasz Huzarski, Jacek Gronwald; CNIO: Ana Osorio, Drakoulis Yannoukakos, Maite Cusido, Javier Benítez; DKFZ: Thomas Dünnebier; HEBON: Frans B.L. Hogervorst, Flora E. van Leeuwen, Maartje J. Hooning, Christi J. van Asperen, Peter Devilee, Marjolijn Ligtenberg, Rob B. van der Luijt, Cora M. Aalfs, Quinten Waisfisz, Marinus J. Blok; EMBRACE: Douglas Easton, Susan Peock, Margaret Cook, Clare Oliver, Debra Frost, Patricia Harrington, Gareth Evans, Fiona Lalloo, Rosalind Eeles, Louise Izatt, Carol Chu, Diana Eccles, Fiona Douglas, Carole Brewer, Lesley McGuffog; FCCC: Andrew K. Godwin; GEMO: Olga M. Sinilnikova, Dominique Stoppa-Lyonnet, Sylvie Mazoyer, Valérie Bonadona, Christine Lasset, Hélène Dreyfus, Dominique Leroux, Agnès Hardouin, Pascaline Berthet, Tetsuro Noguchi, Hagay Sobol, Etienne Rouleau, Catherine Nogues, Marc Frénay, Laurence Vénat-Bouvet, Evgeny Imyanitov; BCFR: Esther M. John, Saundra S. Buys, Mary Daly, John Hopper, Mary Beth Terry, Alexander Miron, Yosuf Yassin, David Goldgar; MUV: Christian F Singer, Daphne Gschwantler-Kaulich, Georg Pfeiler, Catharina Dressler; CBCS: Thomas v. O. Hansen, ILUH: Bjarni A. Agnarsson; MSKCC: Tomas Kirchhoff, Prodipto Pal, Kenneth Offit; GOG: Marion Piedmonte, Gustavo C. Rodriguez, Katie Wakeley, John F. Boggess, Jack Basil, Peter E. Schwartz, Stephanie V. Blank; OSU CCG: Amanda Ewart Toland; UTBCS: Anna Allavena; GC-HBOC: Beatrix Versmold, Barbara Wappenschmidt, Christoph Engel Alfons Meindl, Stefanie Engert, Norbert Arnold, Britta Fiebig, Bernhard H.F. Weber, Dieter Niederacher, Helmut Deissler, Christian Sutter, Karin Kast, Sabine Preisler-Adams; HCSC: Trinidad Caldes, Miguel de la Hoya; HEBCS: Heli Nevanlinna, Kristiina Aittomäki; INHERIT BRCAs: Jacques Simard; Honglin Song.

The CIMBA genotyping, data management and statistical analysis are supported by Cancer Research UK. ACA is a Cancer Research UK Senior Cancer Research Fellow. We thank Ellen Goode for organizing the distribution of the standard DNA plates, and Claudine Isaacs for access to the data from Georgetown University.

CIMBA collaborating centers:

Breast Cancer Family Registry (BCFR)

This work was supported by the National Cancer Institute, National Institutes of Health under RFA # CA-95-011 and through cooperative agreements with members of the Breast Cancer Family Registry and Principal Investigators, including Cancer Care Ontario (U01 CA69467), Columbia University (U01 CA69398), Fox Chase Cancer Center (U01 CA69631), Huntsman Cancer Institute (U01 CA69446), Huntsman Cancer Institute (U01 CA69446), Northern California Cancer Center (U01 CA69417), University of Melbourne (U01 CA69638), and Research Triangle Institute Informatics Support Center (RFP No. N02PC45022-46). 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 Breast CFR, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the Breast CFR.

Copenhagen Breast Cancer Study (CBCS)

We wish to thank Bent Ejlertsen and Mette K. Andersen for their contributions to the study. This work was supported by the Neye Foundation.

Spanish National Cancer Centre (CNIO)

We thank R.M. Alonso for her excellent technical assistance. The samples studied at CNIO were recruited by the Spanish Consortium for the Study of Genetic Modifiers of BRCA1 and BRCA2. This study was partially supported by Mutua Madrileña and Marató TV Foundations.

Epidemiological study of BRCA1 & BRCA2 mutation carriers (EMBRACE)

DE is the PI of the study. EMBRACE Collaborating Centers are: Coordinating Centre, Cambridge: Susan Peock, Margaret Cook, Clare Oliver, Debra Frost. North of Scotland Regional Genetics Service, Aberdeen: Helen Gregory, Zosia Miedzybrodzka. Northern Ireland Regional Genetics Service, Belfast: Patrick Morrison. West Midlands Regional Clinical Genetics Service, Birmingham: Trevor Cole, Carole McKeown, Amy Taylor. South West Regional Genetics Service, Bristol: Alan Donaldson. East Anglian Regional Genetics Service, Cambridge: Joan Paterson. Medical Genetics Services for Wales, Cardiff: Alexandra Murray, Mark Rogers, Emma McCann. St James’s Hospital, Dublin & National Centre for Medical Genetics, Dublin: John Kennedy, David Barton. South East of Scotland Regional Genetics Service, Edinburgh: Mary Porteous. Peninsula Clinical Genetics Service. Exeter: Carole Brewer, Emma Kivuva, Anne Searle, Selina Goodman. West of Scotland Regional Genetics Service, Glasgow: Rosemarie Davidson, Victoria Murday, Nicola Bradshaw, Lesley Snadden, Mark Longmuir, Catherine Watt. South East Thames Regional Genetics Service, Guys Hospital London: Louise Izatt, Gabriella Pichert, Caroline Langman. North West Thames Regional Genetics Service. Harrow: Huw Dorkins. 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: D Gareth Evans, Fiona Lalloo, Felicity Holt. North East Thames Regional Genetics Service, NE Thames: Alison Male, Anne Robinson. Nottingham Centre for Medical Genetics, Nottingham: Carol Gardiner. Northern Clinical Genetics Service, Newcastle: Fiona Douglas, Oonagh Claber. Oxford Regional Genetics Service, Oxford: Lisa Walker, Diane McLeod. 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, Anita Mitra. North Trent Clinical Genetics Service, Sheffield: Jackie Cook, Oliver Quarrell, Cathryn Bardsley. South West Thames Regional Genetics Service, London: Shirley Hodgson, Sheila Goff, Glen Brice, Lizzie Winchester. Wessex Clinical Genetics Service. Princess Anne Hospital, Southampton: Diana Eccles, Anneke Lucassen, Gillian Crawford, Emma Tyler, Donna McBride. SP, MC, DF and CO are funded by Cancer Research-UK Grants C1287/A10118 and C1287/A8874. The Investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. RE/EB/L D’M are also supported by Cancer Research UK Grant C5047/A8385. DGE and FL are supported by an NIHR grant to the Biomedical Research Centre, Manchester.

Fox Chase Cancer Center (FCCC)

Andrew K. Godwin was funded by SPORE P-50CA83638, U01CA69631, 5U01CA113916, and the Eileen Stein Jacoby Fund.

German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC)

We thank all families for providing samples for this study. This work was supported by grants from the German Cancer Aid (Grant numbers 107054 and 107353).

The GEMO study (Genetic Modifiers of cancer risk in BRCA1/2 mutation carriers: Cancer Genetics Network “Groupe Génétique et Cancer”, Fédération Nationale des Centres de Lutte Contre le Cancer, France): We wish to thank all the GEMO collaborating members for their contribution to this study. The GEMO study was supported by the Ligue National Contre le Cancer and the Association “Le cancer du sein, parlons-en!” Award. GEMO Collaborating Centers are: Coordinating Centres, Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Hospitalier Universitaire de Lyon/Centre Léon Bérard, & UMR5201 CNRS, Université de Lyon, Lyon: Olga Sinilnikova, Laure Barjhoux, Sophie Giraud, Mélanie Léone, Sylvie Mazoyer; and INSERM U509, Service de Génétique Oncologique, Institut Curie, Paris: Dominique Stoppa-Lyonnet, Marion Gauthier-Villars, Claude Houdayer, Virginie Moncoutier, Muriel Belotti, Antoine de Pauw. 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. Centre Léon Bérard, Lyon: Christine Lasset, Valérie Bonadona. Centre François Baclesse, Caen: Agnès Hardouin, Pascaline Berthet. Institut Paoli Calmettes, Marseille: Hagay Sobol, 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, Catherine Nogues. 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: Dominique Leroux, Hélène Dreyfus, Christine Rebischung. CHU de Dijon: Cécile Cassini, Laurence Olivier-Faivre. CHU de St-Etienne: Fabienne Prieur. Hôtel Dieu Centre Hospitalier, Chambéry: Sandra Fert Ferrer. Centre Antoine Lacassagne, Nice: Marc Frénay. CHU de Limoges: Laurence Vénat-Bouvet. Creighton University, Omaha, USA: Henry T. Lynch.

Gynecologic Oncology Group (GOG)

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 were performed by NCI’s Core Genotyping Facility. The technical expertise of Dr. Tim Sheehy and Ms. Amy Hutchinson is gratefully acknowledged.

Hospital Clinico San Carlos (HCSC)

This work was supported by grant RD06/0020/0021 from ISCIII, Spanish Ministry of Science and Innovation

Helsinki Breast Cancer Study (HEBCS)

We thank Drs. Carl Blomqvist and Kirsimari Aaltonen, and Tuomas Heikkinen and R. N. Hanna Jäntti for their help with the patient and sample data. The HEBCS study has been financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (110663), the Finnish Cancer Society, and the Sigrid Juselius Foundation.

Hereditary Breast and Ovarian cancer Working Group, the Netherland (HEBON)

Collaborating centers: Coordinating center: Netherlands Cancer Institute, Amsterdam: Frans Hogervorst, Senno Verhoef, Anouk Pijpe, Laura van ’t Veer, Flora van Leeuwen, Matti Rookus; Erasmus Medical Center, Rotterdam: Margriet Collée, Ans van den Ouweland, Mieke Kriege, Mieke Schutte, Maartje Hooning, Caroline Seynaeve; Leiden University Medical Center, Leiden: Christi van Asperen, Juul Wijnen, Maaike Vreeswijk, Rob Tollenaar, Peter Devilee; Radboud University Nijmegen Medical Center, Nijmegen: Marjolijn Ligtenberg, Nicoline Hoogerbrugge; University Medical Center Utrecht, Utrecht: Margreet Ausems, Rob van der Luijt; Amsterdam Medical Center: Cora Aalfs, Theo van Os; VU University Medical Center, Amsterdam: Hans Gille, Quinten Waisfisz, Hanne Meijers-Heijboer; University Hospital Maastricht, Maastricht: Encarna Gomez-Garcia, Kees van Roozendaal, Marinus Blok; University Medical Center Groningen University: Jan Oosterwijk, Annemieke van der Hout, Marian Mourits; The Netherlands Foundation for the detection of hereditary tumours, Leiden, the Netherlands: Hans Vasen.

The HEBON study is supported by the Dutch Cancer Society grants NKI 1998-1854, NKI 2004-3088 and NKI 2007-3756.

Iceland, Landspitali—University Hospital (ILUH)

Group participation was supported by the Research Fund of Landspitali-University Hospital and the Icelandic association:,,Walking for Breast Cancer Research”.

Interdisciplinary Health Research International Team Breast Cancer susceptibility (INHERIT)

Jacques Simard, Francine Durocher, Rachel Laframboise, Marie Plante, Centre Hospitalier Universitaire de Québec & Laval University,Quebec City, Canada;

Peter Bridge, Jilian Parboosingh, Molecular Diagnostic Laboratory, Alberta Children’s Hospital, Calgary, Canada;

Jocelyne Chiquette, Hôpital du Saint-Sacrement, Quebec City, Canada;

Bernard Lesperance, Roxanne Pichette, Hôpital du Sacré-Coeur de Montréal, Montréal, Canada.

Jacques Simard 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.

The Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab)

We wish to thank 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) 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. ABS and GCT are supported by a NHMRC Senior Research and Senior Principal Research Fellowships, respectively.

Mayo Clinic (MAYO)

The study was supported by the Komen Foundation for the cure, NIH Sponsored Program of Research Excellence (SPORE) (CA116201), and NIH R01a (CA116167, CA128978 and CA122340).

Milan Breast Cancer Study Group (MBCSG)

MBCSG is supported by Fondazione Italiana per la Ricerca sul Cancro (FIRC, Special Project “Hereditary tumors”) and Associazione Italiana per la Ricerca sul Cancro (AIRC). MBCSG acknowledges Marco Pierotti, Daniela Zaffaroni and Carla B. Ripamonti of the Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, Monica Barile of the Istituto Europeo di Oncologia, Milan, Italy, Loris bernard and Laura Tizzoni of the Cogentech, Consortium for Genomic Technologies, Milan, Italy

Modifier Study of Quantitative Effects on Disease (ModSQuaD)

Collaborators: C.I. Szabo (Mayo Clinic College of Medicine, Rochester, MN); Michal Zikan, Petr Pohlreich, Zdenek Kleibl (First Faculty of Medicine, Charles University, Prague, Czech Republic); Lenka Foretova, Machackova Eva, and Lukesova Miroslava (Masaryk Memorial Cancer Institute, Brno, Czech Republic); Kathleen Claes, Kim De Leeneer, Bruce Poppe, Anne De Paepe (Ghent University, Ghent, Belgium).

C.I. Szabo is supported by Susan G. Komen Foundation Basic, Clinical, and Translational Research grant (BCTR0402923) and 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 grant No. 301/08/P103 (to M.Z.). Lenka Foretova, Machackova Eva, and Lukesova Miroslava (Masaryk Memorial Cancer Institute, Brno, Czech Republic) are supported through the Ministry of Health of the CR grant—MZ0 MOU 2005. We acknowledge the contribution of Kim De Leeneer, Kathleen Claes, 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).

National Cancer Institute (NCI)

The research of Drs. MH Greene and PL Mai is 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. Genoptyping of NCI DNA samples were performed by NCI’s Core Genotyping Facility, Gaithersburg, MD.

N.N. Petrov Institute of Oncology (NNPIO)

Evgeny Imyanitov: RFBR grants (08-04-00369, 09-04-90402)

Ontario Cancer Genetics Network (OCGN)

We wish to thank Mona Gill, Lucine Collins, Nalan Gokgoz, Teresa Selander, Nayana Weerasooriya and members of the Ontario Cancer Genetics Network for their contributions to the study.

Ohio State University Clinical Cancer Center (OSU CCG)

This work 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 genotyping plate reads.

Odense University Hospital (OUH)

Dorthe Crüger and Lone Sunde are acknowledged for collecting clinical data from the Danish carriers.

Pisa Breast Cancer Study (PBCS)

Partly funded by Fondazione Cassa di Risparmio di Pisa (fellowship to Grazia Lombardi).

Sheba Medical Centre (SMC)

This work was in part funded by the Israel Cancer Association by a grant to Eitan Friedman

The Swedish BRCA1 and BRCA2 Study (SWE-BRCA)

Collaborators: Per Karlsson, Margareta Nordling, Annika Bergman and Zakaria Einbeigi, Gothenburg, Sahlgrenska University Hospital; Marie Stenmark-Askmalm and Sigrun Liedgren, Linkoping University Hospital; Ake Borg, Niklas Loman, Hakan Olsson, Ulf Kristof-fersson, Helena Jernstrom, 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 Malmer, Henrik Gronberg, Eva-Lena Stattin and Monica Emanuelsson, Umea University Hospital; Hans Ehrencrona, Richard Rosenquist Brandell and Niklas Dahl, Uppsala University Hospital.

University of California Irvine (UCI)

This research was supported by NIH RO! CA74415 to SLN. We thank Linda Steele for participant accrual and data management.

University of Turin Breast Cancer Study (UTBCS)

The work of Anna Allavena was supported by Compagnia di San Paolo (Progetto Oncologia).

Footnotes

This study is conducted on behalf of CIMBA, the Consortium of Investigators of Modifiers of BRCA1/2-Related Cancer: kConFab, UCI, MAYO, MBCSG, ModSQuaD, NCI, NICCC, OCGN, OUH, PBCS, SMC, SWE-BRCA, UPENN, IHCC, CNIO, DKFZ, HEBON, EMBRACE, FCCC, GEMO, BCFR, MUV, CBCS, MSKCC, GOG, OSU CCG, UTBCS, GC-HBOC, HCSC, HEBCS, INHERIT BRCAs.

Contributing and collaborating members of the CIMBA consortium are detailed in Acknowledgements.

Contributor Information

Anna Jakubowska, IHCC (International Hereditary Cancer Centre), Department of Genetics and Pathology, Pomeranian Medical University, Polabska 4, 70-115 Szczecin, Poland.

Dominik Rozkrut, Department of Statistics and Econometrics, School of Economics and Management, University of Szczecin, Szczecin, Poland.

Antonis Antoniou, Cancer Research UK Genetic Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

Ute Hamann, Division of Molecular Genome Analysis, Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Jan Lubinski, IHCC (International Hereditary Cancer Centre), Department of Genetics and Pathology, Pomeranian Medical University, Polabska 4, 70-115 Szczecin, Poland.

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