Abstract
Background
BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and non-genetic modifying factors. In this study we evaluated the putative role of variants in many candidate modifier genes.
Methods
Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n=3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach.
Results
The observed p-values of association ranged between 0.005–1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments.
Conclusion
There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers.
Impact
Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies.
Keywords: BRCA1 BRCA2 mutations, BRCA-mutation carriers, Breast cancer risk, Ovarian cancer risk, Candidate genetic risk modifiers
Introduction
Germline BRCA1 or BRCA2 mutations substantially increase the risk of developing breast and ovarian cancer over those of the general population (1). The penetrance is incomplete and combined with the observed variability in age at cancer diagnosis in carriers of identical mutations, suggests the existence of genetic and/or environmental modifying factors. Direct evidence for genetic modifiers of breast and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers has been provided through genome-wide association studies (GWAS) (2). In parallel, multiple variants in candidate genes that affect BRCA1 or BRCA2 protein expression, act along the same biological pathways, or physically interact with BRCA1 or BRCA2 proteins have been evaluated as putative modifiers of BRCA1/2 mutations (reviewed in 3). However, only a handful of these factors were confirmed and independently validated as “true modifiers” (4). The aim of the present study was to assess the putative modifier effect of 3,248 sequence alterations in 445 candidate genes on breast/ovarian cancer risk in 23,463 BRCA1 and BRCA2 mutation carriers.
Materials and methods
Recruitment and data collection
All study participants were women, >18 years old, carrying a deleterious germline mutation in either BRCA1 or BRCA2. DNA samples and phenotypic data were submitted by 54 study centers participating in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) (5). Recruitment strategies, clinical, demographic, and phenotypic data collected from each participant, and quality control procedures, have previously been reported (4,5). All study participants took part in research studies at the parent institutions under ethically-approved protocols as detailed (4,5).
Sequence variants genotyped
DNA samples were genotyped using the custom Illumina iCOGS array which included 211,155 single nucleotide polymorphisms (SNPs) as previously described (http://www.nature.com/icogs/primer/cogs-project-and-design-of-the-icogs-array/; 6). We report results from 3,248 SNPs from 445 candidate genes proposed by 17 PIs (=projects). The rationale for selecting the SNPs or genes as candidate cancer risk modifiers in BRCA1 and BRCA2 mutation carriers is shown in Table 1. The list of SNPs included in the study and their gene location (if any) is provided in Supplementary Table 1. Genotyping quality control procedures were carried out as reported elsewhere (6).
Table 1.
Description of the 17 projects included in the study.
| Project | Rationale for testing SNPs as risk modifiers for breast cancer and ovarian cancer in BRCA-mutation carriers | Number of SNPs included | Reference |
|---|---|---|---|
| 1 | Previous data suggested that irradiation repsonse genes whose expression is associated with BRCA1 and BRCA2 mutation status are enriched for the presence of common genetic modifiers of breast cancer risk. | 18 | Walker LC et al. Evidence for SMAD3 as a modifier of breast cancer risk in BRCA2 mutation carriers. Breast Cancer Res. 2010;12(6):R102. |
| 2 | X chromosome SNPs shown to be associated with risk of breast cancer in the CGEMS breast cancer study were considered. | 11 | Hunter DJ et al. A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat Genet. 2007 Jul;39(7):870–4. |
| 3 | Previous data suggested that the “del” allele of rs3834129 was associated with increased breast cancer risk in BRCA1-mutation carriers. | 1 | Catucci I et al. The CASP8 rs3834129 polymorphism and breast cancer risk in BRCA1 mutation carriers. Breast Cancer Res Treat. 2011 Feb;125(3):855–60. |
| 4 | Search for risk modifiers of BRCA1 5382insC-mutation carriers was performed by a pooled GWAS in 124 women diagnosed with breast cancer (< 45 years) and 119 unaffected controls (> 50 years at last follow up) from Poland. The highest-ranked SNPs from the pooled GWAS were selected. | 137 | None |
| 5 | The proposed SNPs are related to genes in regulatory T-cell (Treg) cell and myeloid derived suppressor cell (MDSC) pathways. Both pathways play a role in cancer immunosuppression. | 2637 | Schreiber RD et al. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science. 2011;331(6024):1565–1570 |
| 6 | The proposed SNPs were associated with breast density. These SNPs were tested only as modifier of breast cancer risk. | 72 | Steude JS et al. Mammographic density and matrix metalloproteinases in breast tissue. Cancer Microenviron. 2010;3(1):57–65. Guo YP et al. Growth factors and stromal matrix proteins associated with mammographic densities. Cancer Epidemiol Biomarkers Prev. 2001;10(3):243–8. Verheus M et al. Common genetic variation in the IGF-1 gene, serum IGF-I levels and breast density. Breast Cancer Res Treat. 2008;112(1):109–22. Diorio C et al. Genetic polymorphisms involved in insulin-like growth factor (IGF) pathway in relation to mammographic breast density and IGF levels. Cancer Epidemiol Biomarkers Prev. 2008;17(4):880–8. Diorio C et al. Vitamin D pathway polymorphisms in relation to mammographic breast density. Cancer Epidemiol Biomarkers Prev. 2008;17(9):2505–8. |
| 7 | SNPs or (SNPs in) genes, were considerd according to following criteria. a) affecting circadian rhythms; b) interacting with CLOCK; c) involved in binding IGF-I to binding proteins; d) in progesterone receptor gene and previously found associated with BC and OvC risk; e) related to disease treatment. | 20 | Hoffman AE et al. CLOCK in breast tumorigenesis: genetic, epigenetic, and transcriptional profiling analyses. Cancer Res. 2010;70(4):1459–68. Kelemen LE et al. Genetic variation in stromal proteins decorin and lumican with breast cancer: investigations in two case-control studies. Breast Cancer Res. 2008;10(6):R98. Patel AV et al. IGF-1, IGFBP-1, and IGFBP-3 polymorphisms predict circulating IGF levels but not breast cancer risk: findings from the Breast and Prostate Cancer Cohort Consortium (BPC3). PLoS One. 2008;3(7):e2578. |
| 8 | All these SNPs are located in selenoprotein genes and are involved in selenium metabolism; selenium is known to be associated with cancer risk. | 11 | Oestergaard MZ et al. Interactions between genes involved in the antioxidant defence system and breast cancer risk. Br J Cancer. 2006;95(4):525–31. Méplan C et al. Association between Polymorphisms in Glutathione Peroxidase and Selenoprotein P Genes, Glutathione Peroxidase Activity, HRT Use and Breast Cancer Risk. PLoS One. 2013;8(9):e73316. Udler M et al. Common germline genetic variation in antioxidant defense genes and survival after diagnosis of breast cancer. J Clin Oncol. 2007;25(21):3015–23. Sutherland A et al. Polymorphisms in the selenoprotein S and 15-kDa selenoprotein genes are associated with altered susceptibility to colorectal cancer. Genes Nutr. 2010;5(3):215–23. |
| 9 | Previous data suggested that the rs1045485 SNP modified disease penetrance of breast and ovarian cancer in BRCA1 mutation carriers. | 1 | Engel C et al. Association of the variants CASP8 D302H and CASP10 V410I with breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev. 2010;19(11):2859–68. |
| 10 | The proposed SNPs are located within the PARP1 gene that plays a key role in the repair of DNA single-strand breaks. | 3 | Gonçalves A et al. Poly(ADP-ribose) polymerase-1 mRNA expression in human breast cancer: a meta-analysis. Breast Cancer Res Treat. 2011;127(1):273–81. |
| 11 | SNPs were considered because of observations based on evidences of recent positive selection and presence in the same genomic region of genes, a) coding for BRCA1 interacting proteins; b) involved in cancer or breast cancer; c) involved in DNA damage response and interacting with TP53. | 13 | Voight BF et al. A map of recent positive selection in the human genome. PLoS Biol. 2006; 4:e72. Lappalainen T et al. Genomic landscape of positive natural selection in Northern European populations. Eur J Hum Genet. 2010;18(4):471–8. |
| 12 | Steroid hormones such as estrogens play an important role in the etiology of breast cancer contributing to tumor growth by promoting cell proliferation. SNPs in candidate genes involved in sex steroid metabolism were considered. The SNPs were tested also as breast cancer risk modifiers considering estrogen receptor status of BRCA-mutation carriers (see Supplementary Table 3) | 139 | Labrie F et al. Endocrine and intracrine sources of androgens in women: inhibition of breast cancer and other roles of androgens and their precursor dehydroepiandrosterone. Endocr Rev. 2003;24(2):152–82. |
| 13 | RAD51C is a breast cancer gene. SNPs located within, or in close proximity to RAD51C were selected. | 17 | Meindl A et al. Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene. Nat Genet. 2010;42(5):410–4. |
| 14 | The highest-ranked SNPsfrom a GWAS based on 700 hereditary breast cancer cases and 1,200 controls were selected. | 142 | None |
| 15 | SNP rs2981582 in FGFR2 is strongly associated with risk of breast cancer and acting as a risk modifier in BRCA2 mutation carriers. Rs2981582 may also influence the risk of ovarian cancer among BRCA1/2-mutation carriers. This SNP was tested only as modifier of ovarian cancer risk. | 1 | Easton DF et al. Genome-wide association study identifies novel breast cancer susceptibility loci. Nature. 2007;447(7148):1087–1093. Hunter DJ et al. A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat Genet. 2007;39(7): 870–874. Antoniou AC et al. Common breast cancer predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers. Am J Hum Genet. 2008;82(4):937–948. |
| 16 | The rs10895068 SNP in the promoter of the progesterone receptor (PR) gene (+331G/A) has been reported to be associated with endometrial cancer risk. Our previous study in 220 patients from BC and OC familes showed a marginal association of the +331A allele with OC risk. This SNP was tested only as modifier of ovarian cancer risk. | 1 | Vivo ID et al. A functional polymorphism in the promoter of the progesterone receptor gene associated with endometrial cancer risk. Proc Natl Acad Sci U S A. 2002;99(19):12263–12268. Romano A et al. Impact of two functional progesterone receptor polymorphisms (PRP): +331G/A and PROGINS on the cancer risks in familial breast/ovarian cancer. Open Cancer J. 2007;1:1–8. |
| 17 | The proposed SNPs were selected according to the hypothesis that different levels of expression of the remaining normal allele in BRCA2 mutation carriers may be associated with variable penetrance of BRCA2 mutations. | 24 | Maia AT et al. Effects of BRCA2 cis-regulation in normal breast and cancer risk amongst BRCA2 mutation carriers. Breast Cancer Res. 2012;14(2):R63 |
Statistical analysis
Associations were evaluated within a retrospective cohort framework, by modeling the retrospective likelihood of the observed genotypes conditional on the disease phenotypes (4,7). The associations between genotype and breast or ovarian cancer risk were assessed using the 1 d.f. score test statistic based on this retrospective likelihood while accounting for the non-independence among related individuals (8). All analyses were stratified by country of residence and used calendar-year and cohort-specific breast and ovarian cancer incidence rates for BRCA1 and BRCA2 mutation carriers. Details are provided elsewhere (2).
Results
A total of 23,463 mutation carriers were included (15,252 BRCA1, 8,211 BRCA2 carriers), 12,127 with breast cancer (7,797 BRCA1, 4,330 BRCA2 carriers), 3,093 with ovarian cancer (2,462 BRCA1, 631 BRCA2 carriers), and 9,220 cancer-free carriers (5,788 BRCA1, 3,432 BRCA2 carriers). All 3,248 SNPs were tested as genetic risk modifiers for both breast and ovarian cancer in BRCA1 and BRCA2 mutation carriers depending on the selection rationale (Table 1). For each SNP, the number of individuals with genotype data, minor allele frequencies (MAF), values of the X2 score test statistic, approximate hazard ratio (HR) estimates based on the score test statistic (7), overall P values and retrospective likelihood HR are shown in Supplementary Table 2. Since project 12 was based on the hypothesis that estrogens contribute to breast cancer pathogenesis, these 139 SNPs were stratified by somatic estrogen receptor status (Supplementary Table 3). None of the SNPs tested showed significant evidence of association with breast and/or ovarian cancer risk, as a single tested variant or after adjusting for mutiple testing. Indeed, there were fewer associations at a nominal P<0.05 or P<0.01 than would be expected by chance (Table 2).
Table 2.
Observed and expected number of SNPs with p-values <0.05 and <0.01
| Category | Tumor | Number of SNPs tested* | Number of SNPs with p-value<0.01 (expected) | Number of SNPs with p-value<0.05 (expected) |
|---|---|---|---|---|
| BRCA1 | BrCa | 3232 | 25 (32) | 202 (162) |
| BRCA1 | OvCa | 3160 | 13 (32) | 146 (158) |
| BRCA2 | BrCa | 3230 | 5 (32) | 96 (161) |
| BRCA2 | OvCa | 3157 | 6 (32) | 131 (159) |
Not all the 3,248 SNPs were tested in each category/tumor group
Discussion
In this study, there were no discernible effects for the genotyped SNPs on either breast or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. Despite the lack of evidence of association between these specific variants and breast/ovarian cancer risk for BRCA1/BRCA2 mutation carriers, these genes may still modify cancer risk by other sequence alterations that are not represented on the iCOGS platform, by epigenetic alterations in gene expression, or in combination and interaction with other polymorphisms, that in concert have an overall effect on cancer risk.
In conclusion, the genotyped SNPs in the candidate modifier genes evaluated here have no major role in breast or ovarian cancer risk modification in either BRCA1 or BRCA2 mutation carriers. Our results suggest that a candidate gene approach where the selected SNPs have little a priori biological plausibility is of limited value in identifying modifier genes, unlike agnostic genome-wide associations which have been more successful (8). Applying more advanced technologies, (whole exome/genome sequencing) and targeting phenotypically distinct mutation carriers may also offer further insights into modifier genes’ identity.
Supplementary Material
Acknowledgments
This study would not have been possible without the contributions of the following: Per Hall (COGS); Douglas F. Easton, Paul Pharoah, Kyriaki Michailidou, Manjeet K. Bolla, Qin Wang (BCAC), Andrew Berchuck (OCAC), Rosalind A. Eeles, Douglas F. Easton, Ali Amin Al Olama, Zsofia Kote-Jarai, Sara Benlloch (PRACTICAL), Georgia Chenevix-Trench, Antonis Antoniou, Lesley McGuffog, Fergus Couch and Ken Offit (CIMBA), Joe Dennis, Alison M. Dunning, Andrew Lee, and Ed Dicks, Craig Luccarini and the staff of the Centre for Genetic Epidemiology Laboratory, Javier Benitez, Anna Gonzalez-Neira and the staff of the CNIO genotyping unit, Jacques Simard and Daniel C. Tessier, Francois Bacot, Daniel Vincent, Sylvie La Boissière and Frederic Robidoux and the staff of the McGill University and Génome Québec Innovation Centre, Stig E. Bojesen, Sune F. Nielsen, Borge G. Nordestgaard, and the staff of the Copenhagen DNA laboratory, and Julie M. Cunningham, Sharon A. Windebank, Christopher A. Hilker, Jeffrey Meyer and the staff of Mayo Clinic Genotyping Core Facility.
We thank Sabine Behrens and Ursula Eilber for excellent technical assistance
Breast Cancer Family Registry (BCFR): We wish to thank members and participants in the Ontario Cancer Genetics Network for their contributions to the study.
BRCA-gene Mutations and Breast Cancer in South African Women (BMBSA): We wish to thank the families who contributed to the BMBSA study.
Beckman Research Institute of the City of Hope (BRICOH): We wish to thank Linda Steele for her work in participant enrollment and biospecimen and data management.
Centro Nacional de Investigaciones Oncológicas (CNIO): We thank Alicia Barroso, Rosario Alonso and Guillermo Pita for their assistance.
Consorzio Studi Italiani sui Tumori Ereditari alla Mammella (CONSIT TEAM): We wish to thank Irene Feroce and Alessandra Rossi of the Istituto Europeo di Oncologia, Milan, Italy; Liliana Varesco of the IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy; Stefania Tommasi and Brunella Pilato of the Istituto Nazionale Tumori “Giovanni Paolo II” - Bari, Italy; Loris Bernard and the personnel of the Cogentech Cancer Genetic Test Laboratory, Milan, Italy.
Epidemiological study of BRCA1 & BRCA2 mutation carriers (EMBRACE): Douglas F. Easton is the PI of the study. EMBRACE Collaborating Centres are: Coordinating Centre, Cambridge: Debra Frost, Steve Ellis, Radka Platte, Jo Perkins. North of Scotland Regional Genetics Service, Aberdeen: Zosia Miedzybrodzka, Helen Gregory. Northern Ireland Regional Genetics Service, Belfast: Patrick Morrison, Lisa Jeffers. West Midlands Regional Clinical Genetics Service, Birmingham: Trevor Cole, Kai-ren Ong, Jonathan Hoffman. South West Regional Genetics Service, Bristol: Alan Donaldson, Margaret James. East Anglian Regional Genetics Service, Cambridge: Marc Tischkowitz, Joan Paterson, Sarah Downing, Amy Taylor. Medical Genetics Services for Wales, Cardiff: Alexandra Murray, Mark T. Rogers, Emma McCann. St James’s Hospital, Dublin & National Centre for Medical Genetics, Dublin: M. John Kennedy, David Barton. South East of Scotland Regional Genetics Service, Edinburgh: Mary Porteous, Sarah Drummond. Peninsula Clinical Genetics Service, Exeter: Carole Brewer, Emma Kivuva, Anne Searle, Selina Goodman, Kathryn Hill. West of Scotland Regional Genetics Service, Glasgow: Rosemarie Davidson, Victoria Murday, Nicola Bradshaw, Lesley Snadden, Mark Longmuir, Catherine Watt, Sarah Gibson, Eshika Haque, Ed Tobias, Alexis Duncan. South East Thames Regional Genetics Service, Guy’s Hospital London: Louise Izatt, Chris Jacobs, Caroline Langman. North West Thames Regional Genetics Service, Harrow: Huw Dorkins. Leicestershire Clinical Genetics Service, Leicester: Julian Barwell. Yorkshire Regional Genetics Service, Leeds: Julian Adlard, Gemma Serra-Feliu. Cheshire & Merseyside Clinical Genetics Service, Liverpool: Ian Ellis, Claire Foo. Manchester Regional Genetics Service, Manchester: D. Gareth Evans, Fiona Lalloo, Jane Taylor. North East Thames Regional Genetics Service, NE Thames, London: Lucy Side, Alison Male, Cheryl Berlin. Nottingham Centre for Medical Genetics, Nottingham: Jacqueline Eason, Rebecca Collier. Northern Clinical Genetics Service, Newcastle: Fiona Douglas, Oonagh Claber, Irene Jobson. Oxford Regional Genetics Service, Oxford: Lisa Walker, Diane McLeod, Dorothy Halliday, Sarah Durell, Barbara Stayner. The Institute of Cancer Research and Royal Marsden NHS Foundation Trust: Ros Eeles, Susan Shanley, Nazneen Rahman, Richard Houlston, Elizabeth Bancroft, Elizabeth Page, Audrey Ardern-Jones, Kelly Kohut, Jennifer Wiggins, Elena Castro, 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, Charlotte Eddy, Vishakha Tripathi, Virginia Attard. Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton: Diana Eccles, Anneke Lucassen, Gillian Crawford, Donna McBride, Sarah Smalley.
Fox Chase Cancer Center (FCCC): We thank Ms. JoEllen Weaver and Dr. Betsy Bove for their technical support.
German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC): is deeply grateful to Dr. Sabine Preisler-Adams for providing information and samples.
GFAST: We wish to thank the technical support of Ilse Coene and Brecht Crombez.
Genetic Modifiers of Cancer Risk in BRCA1/2 Mutation Carriers (GEMO) study: National Cancer Genetics Network «UNICANCER Genetic Group», France. 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, Hospices Civils de Lyon - Centre Léon Bérard, & Equipe «Génétique du cancer du sein», Centre de Recherche en Cancérologie de Lyon: Olga Sinilnikova, Sylvie Mazoyer, Francesca Damiola, Laure Barjhoux, Carole Verny-Pierre, Alain Calender, Sophie Giraud, Mélanie Léone; and Service de Génétique Oncologique, Institut Curie, Paris: Dominique Stoppa-Lyonnet, Marion Gauthier-Villars, Bruno Buecher, Claude Houdayer, Virginie Moncoutier, Muriel Belotti, Carole Tirapo, Antoine de Pauw. Institut Gustave Roussy, Villejuif: Brigitte Bressac-de-Paillerets, Olivier Caron. Centre Jean Perrin, Clermont–Ferrand: Yves-Jean Bignon, Nancy Uhrhammer. Centre Léon Bérard, Lyon: Christine Lasset, Valérie Bonadona, Sandrine Handallou. Centre François Baclesse, Caen: Agnès Hardouin, Pascaline Berthet. Institut Paoli Calmettes, Marseille: Hagay Sobol, Violaine Bourdon, Tetsuro Noguchi, Audrey Remenieras, François Eisinger. CHU Arnaud-de-Villeneuve, Montpellier: Isabelle Coupier, Pascal Pujol. Centre Oscar Lambret, Lille: Jean-Philippe Peyrat, Joëlle Fournier, Françoise Révillion, Philippe Vennin, Claude Adenis. Hôpital René Huguenin/Institut Curie, St Cloud: Etienne Rouleau, Rosette Lidereau, Liliane Demange, Catherine Nogues. Centre Paul Strauss, Strasbourg: Danièle Muller, Jean-Pierre Fricker. Institut Bergonié, Bordeaux: Emmanuelle Barouk-Simonet, Françoise Bonnet, Virginie Bubien, Nicolas Sevenet, Michel Longy. Institut Claudius Regaud, Toulouse: Christine Toulas, Rosine Guimbaud, Laurence Gladieff, Viviane Feillel. CHU Grenoble: Dominique Leroux, Hélène Dreyfus, Christine Rebischung, Magalie Peysselon. CHU Dijon: Fanny Coron, Laurence Faivre. CHU St-Etienne: Fabienne Prieur, Marine Lebrun, Caroline Kientz. Hôtel Dieu Centre Hospitalier, Chambéry: Sandra Fert Ferrer. Centre Antoine Lacassagne, Nice: Marc Frénay. CHU Limoges: Laurence Vénat-Bouvet. CHU Nantes: Capucine Delnatte. CHU Bretonneau, Tours: Isabelle Mortemousque. Groupe Hospitalier Pitié-Salpétrière, Paris: Florence Coulet, Chrystelle Colas, Florent Soubrier. CHU Vandoeuvre-les-Nancy : Johanna Sokolowska, Myriam Bronner. CHU Besançon: Marie-Agnès Collonge-Rame, Alexandre Damette. Creighton University, Omaha, USA: Henry T. Lynch, Carrie L. Snyder.
Helsinki Breast Cancer Study (HEBCS): We would like to thank Taru A. Muranen, Drs. Carl Blomqvist and Kirsimari Aaltonen and RNs Irja Erkkilä and Virpi Palola for their help with the HEBCS data and samples.
The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON) 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, R. Wijnands; Erasmus Medical Center, Rotterdam, NL: J.M. Collée, A.M.W. van den Ouweland, M.J. Hooning, C. Seynaeve, C.H.M. van Deurzen, I.M. Obdeijn; Leiden University Medical Center, NL: C.J. van Asperen, J.T. Wijnen, R.A.E.M. 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 Netherlands Cancer Registry: S. Siesling; The Dutch Pathology Registry (PALGA): L.I.H. Overbeek. HEBON thanks the registration teams of the Comprehensive Cancer Centre Netherlands and Comprehensive Centre South (together the Netherlands Cancer Registry) and PALGA (Dutch Pathology Registry) for part of the data collection.
Molecular Genetic Studies of Breast and Ovarian Cancer in Hungary (HUNBOCS): We wish to thank the Hungarian Breast and Ovarian Cancer Study Group members (Janos Papp, Tibor Vaszko, Aniko Bozsik, Timea Pocza, Judit Franko, Maria Balogh, Gabriella Domokos, Judit Ferenczi, Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary) and the clinicians and patients for their contributions to this study.
University Hospital Vall d’Hebron (HVH): We wish to thank the Oncogenetics Group, and the High Risk and Cancer Prevention Unit of the University Hospital Vall d’Hebron led by Dr. J. Balmaña.
Institut Catala d’Oncologia (ICO): We wish to thank the ICO Hereditary Cancer Program team team led by Dr. Gabriel Capella.
Interdisciplinary Health Research Internal Team Breast Cancer Susceptibility (INHERIT): We would like to thank Dr Martine Dumont, Martine Tranchant for sample management and skillful technical assistance. J.S. is Chairholder of the Canada Research Chair in Oncogenetics. J.S. and P.S. were part of the QC and Genotyping coordinating group of iCOGS (BCAC and CIMBA).
Kathleen Cuningham 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 for their contributions to this resource, and the many families who contribute to kConFab. Georgia Chenevix-Trench and Amanda B Spurdle are NHMRC Senior Research Fellows
Memorial Sloan-Kettering Cancer Center (MSKCC): We wish to thank Anne Lincoln.
Ontario Cancer Genetics Network (OCGN): We wish to thank members and participants in the Ontario Cancer Genetics Network for their contributions to the study.
The Ohio State University Comprehensive Cancer Center (OSUCCG): Leigha Senter, Kevin Sweet, Caroline Craven, and Michelle O’Connor were instrumental in accrual of study participants, ascertainment of medical records and database management. Samples were processed by the OSU Human Genetics Sample Bank.
Sheba Medical Centre (SMC): SMC team wishes to acknowledge the assistance of the Meirav Comprehensive breast cancer center team at the Sheba Medical Center for assistance in this study.
Swedish Breast Cancer Study (SWE-BRCA): Swedish scientists participating as SWE-BRCA collaborators are Anna von Wachenfeldt, Annelie Liljegren, Annika Lindblom, Brita Arver, Gisela Barbany Bustinza and Johanna Rantala (Karolinska University Hospital); Marie Stenmark-Askmalm and Sigrun Liedgren (Linköping University); Ake Borg, Helena Jernström and Katja Harbst (Lund University); Håkan Olsson, Karin Henriksson, Maria Soller, Niklas Loman and Ulf Kristoffersson (Lund University Hospital); Anna Öfverholm, Margareta Nordling, Per Karlsson and Zakaria Einbeigi (Sahlgrenska University Hospital); Beatrice Melin, Christina Edwinsdotter Ardnor and Monica Emanuelsson (Umeå University); Maritta Hellström Pigg and Richard Rosenquist (Uppsala University); Hans Ehrencrona (Uppsala University and Lund University Hospital).
Financial support: Funding for the iCOGS infrastructure came from: the European Community’s Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. BCFR was supported by grant UM1 CA164920 from the National Cancer Institute. 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 Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the BCFR; BFBOCC is partly supported by: Research Council of Lithuania grant LIG-07/2012; BRCA-gene mutations and breast cancer in South African women (BMBSA) was supported by grants from the Cancer Association of South Africa (CANSA) to Elizabeth J. van Rensburg; the CNIO study was supported by Spanish Association against Cancer (AECC08), RTICC 06/0020/1060 and FISPI12/00070 and Mutua Madrileña Foundation (FMMA); City of Hope Clinical Cancer Genetics Community Network and the Hereditary Cancer Research Registry (COH-CCGCRN) is supported in part by Award Number RC4CA153828 (PI: J. Weitzel) from the National Cancer Institute and the Office of the Director, National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health; CONSIT TEAM was partially supported by funds from Italian citizens who allocated the 5×1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale dei Tumori, according to Italian laws (INT-Institutional strategic projects ‘5×1000’); the DKFZ study was supported by the DKFZ; EMBRACE is supported by Cancer Research UK Grants C1287/A10118, C1287/A16563 and C1287/A17523. D. Gareth Evans and Fiona Lalloo are supported by an NIHR grant to the Biomedical Research Centre, Manchester. 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. Ros Eeles and Elizabeth Bancroft are supported by Cancer Research UK Grant C5047/A8385; the German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC) is supported by the German Cancer Aid (grant no 109076, Rita K. Schmutzler) and by the Center for Molecular Medicine Cologne (CMMC); the GEMO study was supported by the Ligue National Contre le Cancer; the Association “Le cancer du sein, parlons-en!” Award; and the Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program; the HEBCS was financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society and the Sigrid Juselius Foundation; The HEBON study is supported by the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, the Netherlands Organization of Scientific Research grant NWO 91109024, the Pink Ribbon grant 110005 and the BBMRI grant NWO 184.021.007/CP46; Hungarian Breast and Ovarian Cancer Study (HUNBOCS) was supported by Hungarian Research Grants KTIA-OTKA CK-80745 and OTKA K-112228; ICO was sponsored by Asociación Española Contra el Cáncer, Spanish Health Research Fund; Carlos III Health Institute; Catalan Health Institute and Autonomous Government of Catalonia, contract grant numbers: ISCIIIRETIC RD06/0020/1051, RD12/0036/008, PI10/01422, PI10/00748 and 2009SGR290; The IHCC was supported by Grant PBZ_KBN_122/P05/2004; The ILUH group was supported by the Icelandic Association “Walking for Breast Cancer Research” and by the Landspitali University Hospital Research Fund; IOVHBOCS is supported by Ministero della Salute and “5×1000” Istituto Oncologico Veneto grant; 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; MAYO is supported by NIH grant CA128978, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a U.S. Department of Defence Ovarian Cancer Idea award (W81XWH-10-1-0341) and a grant from the Breast Cancer Research Foundation, the David and Margaret T. Grohne Family Foundation, and the Ting Tsung and Wei Fong Chao Foundation; MSKCC is supported by grants from the Breast Cancer Research Foundation and Robert and Kate Niehaus Clinical Cancer Genetics Initiative; OSUCCG is supported by the Ohio State University Comprehensive Cancer Center; SWE-BRCA collaborators are supported by the Swedish Cancer Society; the Women’s Cancer Program (WCP) at the Samuel Oschin Comprehensive Cancer Institute is funded by the American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN).
This work was supported by the NEYE Foundation; by the European Union (European Social Fund – ESF) and Greek national funds through the Operational Program “Education and Lifelong Learning” of the National Strategic Reference Framework (NSRF) - Research Funding Program of the General Secretariat for Research & Technology: ARISTEIA, Investing in knowledge society through the European Social Fund; by the University of Kansas Cancer Center (P30 CA168524) and the Kansas Bioscience Authority Eminent Scholar Program; by National Cancer Institute grants to the Gynecologic Oncology Group (GOG) Administrative Office and Tissue Bank (CA 27469), the GOG Statistical and Data Center (CA 37517), and by NCI’s Community Clinical Oncology Program (CCOP) grant (CA 101165); by the Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program, the Canadian Breast Cancer Research Alliance-grant #019511 and the Ministry of Economic Development, Innovation and Export Trade – grant # PSR-SIIRI-701; through a grant by the Israel Cancer Association and the funding for the Israeli Inherited Breast Cancer Consortium; by National Institutes of Health (NIH) (R01-CA102776 and R01-CA083855; by Breast Cancer Research Foundation; by Susan G. Komen Foundation; by Basser Research Center; by RD12/00369/0006 from ISCIII and the European Regional Development funds, Spain and by 1R01 CA149429-01 grant.
Susan L. Neuhausen was partially supported by the Morris and Horowitz Families Endowed Professorship; Andrew K. Godwin was funded by 5U01CA113916, R01CA140323, and by the Chancellors Distinguished Chair in Biomedical Sciences Professorship; the research of Mark H Greene and Phuong L Mai was supported by the Intramural Research Program of the US National Cancer Institute, NIH, and by support services contracts NO2-CP-11019-50 and N02-CP-65504 with Westat, Inc, Rockville, MD.
Footnotes
Disclosure of potential conflict of interest: All authors declare that they have no conflicts of interest.
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