Abstract

Germline mutations inBRCA1 andBRCA2 confer high risks of breast cancer. However, evidence suggests that these risks are modified by other genetic or environmental factors that cluster in families. A recent genome-wide association study has shown that common alleles at single nucleotide polymorphisms (SNPs) inFGFR2 (rs2981582),TNRC9 (rs3803662), andMAP3K1 (rs889312) are associated with increased breast cancer risks in the general population. To investigate whether these loci are also associated with breast cancer risk inBRCA1 andBRCA2 mutation carriers, we genotyped these SNPs in a sample of 10,358 mutation carriers from 23 studies. The minor alleles of SNP rs2981582 and rs889312 were each associated with increased breast cancer risk inBRCA2 mutation carriers (per-allele hazard ratio [HR] = 1.32, 95% CI: 1.20–1.45, p_trend = 1.7 × 10⁻⁸ and HR = 1.12, 95% CI: 1.02–1.24, p_trend = 0.02) but not inBRCA1 carriers. rs3803662 was associated with increased breast cancer risk in bothBRCA1 andBRCA2 mutation carriers (per-allele HR = 1.13, 95% CI: 1.06–1.20, p_trend = 5 × 10⁻⁵ inBRCA1 and BRCA2 combined). These loci appear to interact multiplicatively on breast cancer risk inBRCA2 mutation carriers. The differences in the effects of theFGFR2 andMAP3K1 SNPs betweenBRCA1 andBRCA2 carriers point to differences in the biology ofBRCA1 andBRCA2 breast cancer tumors and confirm the distinct nature of breast cancer inBRCA1 mutation carriers.

Introduction

BRCA1 (MIM113705) andBRCA2 (MIM600185) mutations confer high risks of breast and other cancers. A meta-analysis of mutation-positive families identified through population-based studies of breast or ovarian cancer estimated the risk of breast cancer by age 70 years to be 65% and 45% forBRCA1 andBRCA2 mutation carriers, respectively.¹ Although the pattern of risk was similar, the absolute magnitude of risk in that study was lower than in previously published studies based on families with multiple affected individuals, in particular forBRCA2 mutation carriers.² The breast cancer risks inBRCA1 andBRCA2 mutation carriers have also been found to vary by the age at diagnosis and the type of cancer (unilateral breast cancer, contralateral breast cancer, or ovarian cancer) in the index patient.^1,3,4 Such observations are consistent with the hypothesis that breast cancer risks inBRCA1 andBRCA2 mutation carriers are modified by other genetic or environmental factors that cluster in families.^1,3 Further evidence of genetic modifiers of risk comes from segregation-analysis models that have quantified the extent of variability in the risk of breast cancer in mutation carriers in terms of a polygenic-modifying variance^5,6. In addition, Begg et al.³ demonstrated significant between-family variation in risk.

A number of studies have evaluated associations between genetic variants and breast cancer risk inBRCA1 andBRCA2 mutation carriers^7,8, but apart from a recent CIMBA (Consortium of Investigators of Modifiers ofBRCA1/2) study that found evidence of association amongBRCA2 mutation carriers who are rare homozygotes for a single nucleotide polymorphism (SNP) inRAD51, no other such associations have been reliably identified.⁹ A recent genome-wide association study in breast cancer identified five common susceptibility alleles that are associated with an increased risk of breast cancer in the general population.¹⁰ To address whether these polymorphisms are also associated with the risk of breast cancer inBRCA1 andBRCA2 mutation carriers, we typed the three SNPs with the strongest evidence of association inBRCA1 andBRCA2 mutation carriers from the CIMBA study.⁷

Material and Methods

Results

Results are shown inTable 3. SNP rs2981582 inFGFR2 was associated with breast cancer risk in the combined sample ofBRCA1 andBRCA2 mutation carriers (p_trend = 0.0001). However, whenBRCA1 andBRCA2 carriers were analyzed separately, the association was restricted toBRCA2 mutation carriers (p_trend = 2 × 10⁻⁸), and there was no evidence of an association amongBRCA1 carriers (p_trend = 0.6; p = 1.3 × 10⁻⁵ for the difference in the estimates betweenBRCA1 andBRCA2 carriers). The estimated effect amongBRCA2 mutation carriers was consistent with a multiplicative model in which each copy of the disease allele conferred a hazard ratio (HR) of 1.32 (95%CI: 1.20–1.45) (Figure 1). There was some suggestion that the HRs might differ between studies forBRCA1 (p = 0.03), but there was no evidence of heterogeneity forBRCA2 (p = 0.11).

TNRC9 SNP rs3803662 was associated with an increased risk of breast cancer in bothBRCA1 andBRCA2 mutation carriers (p_trend = 0.004 and 0.009, respectively; joint p_trend = 0.00005). The per-allele HR was estimated to be 1.11 (95%CI: 1.03–1.19) forBRCA1 carriers and 1.15 (95%CI: 1.03–1.27) forBRCA2 carriers (p = 0.6 for the difference in theBRCA1 andBRCA2 per-allele HR estimates). There was no evidence of heterogeneity in the HRs among studies (BRCA1: p = 0.67;BRCA2: p = 0.63,Figure 2).

There was no evidence that SNP rs889312 inMAP3K1 was associated with breast cancer risk in the combined sample ofBRCA1 andBRCA2 mutation carriers or inBRCA1 carriers alone (p_trend = 0.29 and 0.86, respectively). However,BRCA2 mutation carriers who carried a copy of the minor allele of this SNP were at increased risk of breast cancer (per-allele HR = 1.12, 95% CI: 1.02–1.24, p_trend = 0.02). There was some evidence of heterogeneity in the HRs between studies forBRCA2 (p = 0.02) but not forBRCA1 (p = 0.06) mutation carriers (Figure 3). We also investigated whether the HRs change with age by including an age × genotype interaction term in the model. There was no significant evidence that HRs vary by age for any of the variants.

If these SNPs were associated with disease survival in carriers, the estimated HRs might be affected by the inclusion of prevalent cancer cases. We therefore repeated our analysis after excluding cancer cases diagnosed more than five years prior to their study recruitment. A total of 7,027BRCA1 andBRCA2 mutation carriers were eligible for this analysis (2,523 affected; 4,504 unaffected). The estimated per-allele HRs amongBRCA2 mutation carriers were virtually unchanged for theFGFR2 SNP rs2981582 (per-allele HR 1.37 (95%CI: 1.22–1.54; p_trend = 2 × 10⁻⁷) and theMAP3K1 SNP rs889312 (HR: 1.11, 95%CI: 0.98–1.25, p_trend = 0.11), but slightly higher for theTNRC9 SNP rs3803662 (BRCA1: 1.17 (95% CI:1.06-1.28, p_trend = 0.001;BRCA2: 1.24 (95%CI: 1.10–1.41, p_trend = 0.0008;BRCA1andBRCA2 combined p_trend = 9 × 10⁻⁷).

Risk-reducing salpingo-oophorectomy (RRSO) reduces the risk of breast cancer inBRCA1 andBRCA2 mutation carriers.^11,12 To investigate whether allowance for RRSO alters our results in any way, we repeated the analysis after censoring theBRCA1 andBRCA2 mutation carriers at the time of surgery. Because information on RRSO was missing for approximately 30% of the carriers, we performed this analysis by first including all carriers in the analysis and assuming that carriers with no RRSO information did not have the surgery; we then repeated the analysis after including only carriers with data on RRSO as previously described.⁹ When allBRCA1 andBRCA2 mutation carriers were included in this analysis, the HRs and significance test results were very similar to results of the analysis in which no censoring at RRSO took place (Table S1 in theSupplemental Data). When carriers with no information on RRSO were excluded, the sample size was reduced from 10,358 to 7,190. The estimated HRs remained virtually identical to those in the primary analysis, although the p values were increased, because of a reduced sample size (Table S1; rs2981582 inBRCA2: p_trend = 6 × 10⁻⁶; rs3803662 inBRCA1,BRCA2 and combined: p_trend = 0.03, 0 .02, 0.001 respectively; rs889312 inBRCA2: p_trend = 0.16).

BRCA1 andBRCA2 mutations are also associated with increased risks of ovarian cancer.¹ Carriers who had developed ovarian cancer were included in our analyses as unaffected. A possible bias could have been introduced if these SNPs were associated with ovarian cancer risk. Although there is no evidence of such an association in the general population (American Society of Human Genetics meeting 2007, San Diego, USA, Abstract 428), we repeated our analyses by excluding the 975 mutation carriers who were censored at an ovarian cancer diagnosis. The estimated HRs were unchanged (Table S2).

To evaluate the potential combined effects of the two most significant SNPs on breast cancer risk inBRCA2 mutation carriers, we fitted a multiplicative model (log additive, 2 degrees of freedom [df]) for the effects of theFGFR2 SNP rs2981582 andTNRC9 SNP rs3803662 and compared this against a fully saturated model in which a separate parameter was fitted for eachFGFR2-TNRC9 combined genotype (8 df). The HR estimates for all nine genotypes under the multiplicative and fully saturated models are shown inTable 4. The HRs were remarkably similar under the two models, and there was no significant evidence that the fully saturated model fit better than the multiplicative model (χ² = 4.48, df = 6, p-value:0.61). Under the multiplicative model, the highest HR was 2.26 for carriers who were homozygotes for the risk allele at both loci in comparison toBRCA2 carriers who did not have any risk alleles. Based on the minor allele frequencies of theFGFR2 andTNRC9 SNPs in the general population,¹⁰ approximately 36% of the BRCA2 mutation carriers will have HRs in excess of 1.5 in comparison to the 20% of carriers who will have no copies of the disease allele at eitherFGFR2 orTNRC9.

Discussion

Our results provide strong evidence that SNP rs2981582 inFGFR2 is associated with breast cancer risk inBRCA2 mutation carriers and that SNP rs3803662 inTNRC9 is associated with breast cancer risk in bothBRCA1 andBRCA2 mutation carriers. With our sample size, we can rule out a comparable involvement of rs2981582 in the breast cancer risk forBRCA1 mutation carriers. These results were unaltered when we accounted for survival bias and risk-reducing salpingo-oophorectomy or when we included ovarian cancer cases as unaffected in the analysis. There was no evidence of heterogeneity in the HRs between studies. The evidence of association with SNP rs889312 inMAP3K1 was weaker and was restricted toBRCA2 mutation carriers. For all three SNPs, the estimated HRs inBRCA2 carriers were very similar to the corresponding estimated odds ratios (OR) for breast cancer derived from data from large population-based case-control studies¹⁰ (per-allele ORs: 1.26, 1.20 and 1.13 for rs2981582 [FGFR2], rs3803662 [TNRC9], and rs889312 [MAP3K1], respectively). Based on the per-allele HR estimates, the frequencies of the risk alleles in the general population¹⁰ and recent estimates of the genetic variance of the breast cancer risks inBRCA1 andBRCA2 mutation carriers (“modifying variance”) derived from breast cancer segregation analyses⁶, theTNRC9 SNP is predicted to account for approximately 0.5% of theBRCA1 modifying variance. The SNPs inFGFR2,TNRC9, andMAP3K1 are estimated to account for 2.8% of theBRCA2 modifying variance.

It has been reported that more than 90% ofBRCA1 breast cancer tumors are estrogen receptor (ER) negative, whereasBRCA2 breast cancer tumors have an ER distribution similar to that in the general population, in which the majority are ER positive.¹⁹ A recent Breast Cancer Association Consortium study found that theFGFR2 SNP rs2981582 was more strongly associated with ER-positive breast cancers than ER-negative tumors (OR: 1.31 versus 1.08, respectively).²⁰ The same study found that theTNRC9 SNP rs3803662 was associated with the risk of both ER-positive and ER-negative breast cancers, which is again consistent with our results. Therefore, our results are consistent with the hypothesis that the SNPs modify the risk of breast cancer to a similar, relative extent in carriers for eitherBRCA2 or (in the case ofTNRC9 rs3803662)BRCA1 and noncarriers. The weaker (or null) effect inBRCA1 carriers for theFGFR2 SNP rs2981582 is explicable by its weak effect on ER negative disease and is further confirmation of the distinct nature of breast cancer inBRCA1 mutation carriers.

One potential limitation of this study is that it was not possible to take the precise family histories of carriers into account because CIMBA does not currently collect this information. Although this does not invalidate the statistical tests of association, we could not therefore assess directly how the breast cancer risk in carriers associated with these SNPs varies by the degree of family history. Such effects might be important in the context of genetic counseling. Another limitation is that we did not have detailed tumor characteristics such as ER status available for our carriers. For example, it might be that theFGFR2 SNP is associated with the risk of ER-positive breast cancer in BRCA1 carriers, but this is not observable in our dataset because they only account for a small fraction of cases. In addition, information on whether any of the mutation carriers were on chemoprevention was also not available. However, chemoprevention is not expected to be a confounder in our analyses because its use is unlikely to be associated with the SNPs under investigation. A final uncertainty is that the SNPs we have tested are probably not the variants causally related to the disease, but are correlated with them. This does not invalidate the associations, but it might mean that the associations with the causal variants, when they are identified, will prove to be somewhat stronger.

BecauseBRCA1 andBRCA2 mutations confer high risks, the modest HRs associated with these SNPs translate into marked differences in absolute risk between extreme genotypes. For example, the absolute risk of breast cancer by age 70 amongBRCA2 mutation carriers is predicted to be 43% for common homozygotes at theFGFR2 locus and 63% for rare homozygotes. The corresponding risks forTNRC9 are 48% and 58% for common and rare homozygotes, respectively. However, when the combined effects of the two loci are considered, the absolute risk varies from 41% (for carriers with no risk alleles) to 70% (for carriers with four risk alleles; seeFigure 4). Although only 1% of carriers are doubly homozygous, approximately 36% of carriers will have a HR of 1.5 or greater in comparison to the 20% of carriers with no risk alleles. This corresponds to an absolute risk of 55% or greater by age 70. If further such risk alleles are identified (for example, through additional genome scans), the proportion of carriers for whom the risk can be modified substantially will increase. These risks might also be affected by other factors, including family history, mutation type, and lifestyle risk factors, and future studies should aim to investigate these effects.

Supplemental Data

Two additional tables are available online athttp://www.ajhg.org/.

Supplemental Data

Web Resources

The URLs for data presented herein are as follows:

• Breast Cancer Information Core (BIC),http://research.nhgri.nih.gov/projects/bic/

• Online Mendelian Inheritance in Man,http://www.ncbi.nlm.nih.gov/Omim

Acknowledgments

A.C.A., K.A.P., and the CIMBA data management are funded by Cancer Research-UK. D.F.E. is a principal research fellow of Cancer Research-UK. We thank Ellen Goode for organizing the distribution of the standard DNA plates.

CIMBA Collaborating Centres:

German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC). GC-HBOC is supported by a grant of the German Cancer Aid (grant 107054) and the Center for Molecular Medicine Cologne (grant TV93) to R.K.S.

Hospital Clinico San Carlos (HCSC). T.C. is funded by FMMA/06 and RTICC06/0003/0021 HCSC-Spain.

Helsinki Breast Cancer Study (HEBCS). HEBCS was supported by the Academy of Finland (110663), Helsinki University Central Hospital Research Fund, the Sigrid Juselius Fund, and the Finnish Cancer Society. We thank Tuomas Heikkinen for his contribution in the molecular analyses and Kristiina Aittomäki, Kirsimari Aaltonen, and Carl Blomqvist for their help in patient sample and data collection.

Interdisciplinary Health Research International Team Breast Cancer Susceptibility (INHERIT). Jacques Simard, Francine Durocher, Rachel Laframboise, and Marie Plante, Centre Hospitalier Universitaire de Quebec & Laval University, Quebec, Canada; Peter Bridge, and Jilian Parboosingh Molecular Diagnostic Laboratory, Alberta Children's Hospital, Calgary, Canada; Jocelyne Chiquette, Hôpital du Saint-Sacrement, Quebec, Canada; Bernard Lesperance and Roxanne Pichette, Hôpital du Sacré-Cœur de Montréal, Quebec, Canada. This work was supported by the Canadian Institutes of Health Research for the INHERIT BRCAs program, the CURE Foundation, and the Fonds de la recherche en Santé du Quebec/Reseau de Medecine Genetique Appliquee.

The Kathleen Cuningham Consortium for Research into Familial Breast Cancer (kConFab). We wish to thank Heather Thorne, Eveline Niedermayr, Helene Holland, 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 and 288704) for their contributions to this resource, as well as the many families who contribute to kConFab. kConFab is supported by grants from the National Breast Cancer Foundation and 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. A.B.S. and G.C.T. are a NHMRC Career Development awardee and a senior principal research fellow, respectively.

Modifiers and Genetics in Cancer (MAGIC). Support was received from NIH grants R01-CA083855 and R01-CA74415 (to S.L.N.) and grants R01-CA102776 and R01-CA083855 (to T.R.R.). Support was also received from grant NCI P30 CA51008-12 (to C.I.). This article was supported by revenue from Nebraska cigarette taxes awarded to Creighton University by the Nebraska Department of Health and Human Services. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the State of Nebraska or the Nebraska Department of Health and Human Services. Support was also given by the National Institutes of Health through grant #1U01 CA 86389. Henry Lynch's work is partially funded through the Charles F. and Mary C. Heider Chair in Cancer Research, which he holds at Creighton University. The hereditary cancer registry at City of Hope (J.W.) is supported in part by a General Clinical Research Center grant (M01 RR00043) awarded by the NIH to the City of Hope National Medical Center, Duarte, California.

Mayo Clinic Study (MAYO). The Mayo Clinic study was supported by the Breast Cancer Research Foundation (BCRF), U.S. Army Medical Research and Materiel Command (W81XWH-04-1-0588), the Mayo Clinic Breast Cancer SPORE (P50-CA116201), and NIH grant CA122340 to F.J.C. We wish to thank Noralane Lindor and Linda Wadum for their contributions.

Milan Breast Cancer Study Group (MBCSG). MBCSG is supported by Fondazione Italiana per la Ricerca sul Cancro (FIRC, Special Project “Hereditary tumors”). MBCSG acknowledges Marco Pierotti of the Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy and Bernardo Bonanni of the Istituto Europeo di Oncologia, Milan, italy.

Modifier Study of Quantitative Effects on Disease (Mod-SQuaD). C.I.S. is partially supported by a Susan G. Komen Foundation Basic. Clinical, and Translational Research Grant (BCTR0402923). Research Project of the Ministry of Education, Youth and Sports of the Czech Republic No. MSM0021620808 to Michal Zikan, Zdenek Kleibl, and Petr Pohlreich. We acknowledge the contributions of Michal Zikan, Petr Pohlreich and Zdenek Kleibl (Department of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University Prague, Czech Republic) and Lenka Foretova, Machakova Eva, and Lukesova Miroslava (Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic).

National Cancer Institute study (NCI). We acknowledge the contributions of Jeffery Struewing and Marbin A Pineda from the Laboratory of Population Genetics. Greene and Struewing were supported by funding from the Intramural Research Program of the National Cancer Institute. Their data-collection efforts were supported by contracts NO2-CP-11019-50 and N02-CP-65504 with Westat, Inc, Rockville, MD.

Ontario Cancer Genetics Network (OCGN) study. We thank Mona Gill for excellent technical assistance and acknowledge funding from Cancer Care Ontario and the National Cancer Institute of Canada with funds from the Terry Fox Run.

Odense University Hospital (OUH) study. The Danish Cancer Research Fund supported the Danish group at Odense University Hospital. Mads Thomassen is greatly acknowledged for performing the genotyping of the Danish samples.

Pisa Breast Cancer Study (PBCS). PBCS acknowledges AIRC the Italian Association for Cancer Research.

University of Pennsylvania (UPENN) study. K.L.N. is supported by the Breast Cancer Research Foundation (BCRF). S.M.D. is supported by QVC Network, the Fashion Footwear Association of New York, and the Marjorie B. Cohen Foundation.

Sheeba Medical Center Study (SMC)

The Swedish BRCA1 and BRCA2 study (SWE-BRCA). SWE-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, Ulf Kristoffersson, Helena Jernström, and Katja Backenhorn, Lund University Hospital; Annika Lindblom, Brita Arver, Anna von Wachenfeldt, Annelie Liljegren, Gisela Barbany-Bustinza, and Johanna Rantala, Stockholm, Karolinska University Hospital; Henrik Grönberg, Eva-Lena Stattin, and Monica Emanuelsson, Umeå University Hospital; Hans Boström, Richard Rosenquist Brandell, and Niklas Dahl, Uppsala University Hospital.

Spanish National Cancer Centre (CNIO). Thanks to Rosario Alonso, Alicia Barroso, and Guillermo Pita for their technical support. The samples studied at the CNIO were recruited by the Spanish Consortium for the Study of Genetic Modifiers ofBRCA1 andBRCA2 (Spanish National Cancer Centre [Madrid], Sant Pau Hospital [Barcelona], Instituto Catalá d`Oncología [Barcelona], Hospital Clínico San Carlos [Madrid], Valladolid University [Madrid], Cancer Research Centre [Salamanca], and Instituto Dexeus [Barcelona]) and the Instituto Demokritos. The work carried out at the CNIO was partly funded by grants from the Genome Spain,Mutual Madrileña andMarató Foundations.

Deutsches Krebsforschungszentrum (DKFZ) study. The DKFZ study was supported by the DKFZ. We thank Diana Torres and Muhammad U. Rashid for providing DNA samples and supplying data. We thank Antje Seidel-Renkert and Michael Gilbert for expert technical assistance.

DNA-HEBON. The following are DNA-HEBON collaborating centers, Netherlands. Coordinating center, Netherlands Cancer Institute, Amsterdam: Frans Hogervorst, Peggy Manders, Matti Rookus, Flora van Leeuwen, Laura van 't Veer, and Senno Verhoef. Erasmus Medical Center, Rotterdam: Ans van den Ouweland, Margriet Collée, and Jan Klijn. Leiden University Medical Center, Leiden: Juul Wijnen and Christi van Asperen. Radboud University Nijmegen Medical Center, Nijmegen: Marjolijn Ligtenberg and Nicoline Hoogerbrugge. VU University Medical Center, Amsterdam: Hans Gille and Hanne Meijers-Heijboer. University Hospital Maastricht, Maastricht: Kees van Roozendaal, Rien Blok, and Encarna Gomez-Garcia. The DNA-HEBON study is part of the HEBON study (HEriditary Breast and Ovarian study Netherlands) andis supported by Dutch Cancer Society grants NKI2004-3088 and NKI2007-3756.

EMBRACE. M.C., S.P., and EMBRACE are funded by Cancer Research-UK. D.F.E. is the PI of the study. The following are EMBRACE collaborating centers. Coordinating Centre, Cambridge: Susan Peock, Margaret Cook, and Alexandra Bignell. North of Scotland Regional Genetics Service, Aberdeen: Neva Haites, Helen Gregory. Northern Ireland Regional Genetics Service, Belfast: Patrick Morrison. West Midlands Regional Clinical Genetics Service, Birmingham: Trevor Cole and Carole McKeown. South West Regional Genetics Service, Bristol: Alan Donaldson. East Anglian Regional Genetics Service, Cambridge: Joan Paterson. Medical Genetics Services for Wales, Cardiff: Alexandra Murray, and Mark Rogers. St James's Hospital, Dublin and National Centre for Medical Genetics, Dublin: Peter Daly and David Barton. South East of Scotland Regional Genetics Service, Edinburgh: Mary Porteous and Michael Steel. Peninsula Clinical Genetics Service. Exeter: Carole Brewer and Julia Rankin. West of Scotland Regional Genetics Service, Glasgow: Rosemarie Davidson and Victoria Murday. South East Thames Regional Genetics Service, Guys Hospital London: Louise Izatt and Gabriella Pichert. North West Thames Regional Genetics Service, Harrow: Huw Dorkins. Leicestershire Clinical Genetics Service, Leicester: Richard Trembath. Yorkshire Regional Genetics Service, Leeds: Tim Bishop and Carol Chu. Merseyside and Cheshire Clinical Genetics Service, Liverpool: Ian Ellis. Manchester Regional Genetics Service, Manchester: D. Gareth Evans, Fiona Lalloo, and Andrew Shenton. North East Thames Regional Genetics Service, NE Thames: Alison Male, James Mackay, and Anne Robinson. Nottingham Centre for Medical Genetics, Nottingham: Carol Gardiner. Northern Clinical Genetics Service, Newcastle: Fiona Douglas and John Burn. Oxford Regional Genetics Service, Oxford: Lucy Side, LIsa Walker, and Sarah Durell. Institute of Cancer Research and Royal Marsden NHS Foundation Trust: Rosalind Eeles. North Trent Clinical Genetics Service, Sheffield: Jackie Cook and Oliver Quarrell. South West Thames Regional Genetics Service, London: Shirley Hodgson. Wessex Clinical Genetics Service. Southampton: Diana Eccles and Anneke Lucassen.

Fox Chase Cancer Center (FCCC). A.K.G. was funded by SPORE P-50 CA 83638, U01 CA69631, 5U01 CA113916, and the Eileen Stein Jacoby Fund.

Genetic Modifiers of cancer risk in BRCA1/2 mutation carriers study (GEMO). The GEMO study was supported by the Programme Hospitalier de Recherche Clinique AOR01082, by Programme Incitatif et Coopératif Génétique et Biologie de Cancer du Sein, Institut Curie and by the Association “Le cancer du sein, parlons-en!” Award.

References

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.