Common variants in LSP1, 2q35 and 8q24 and breast cancer risk for BRCA1 and BRCA2 mutation carriers

Antonis C. Antoniou, Olga M. Sinilnikova, Lesley McGuffog, Sue Healey, Heli Nevanlinna, Tuomas Heikkinen, Jacques Simard, Amanda B. Spurdle, Jonathan Beesley, Xiaoqing Chen, Susan L. Neuhausen, Yuan C. Ding, Fergus J. Couch, Xianshu Wang, Zachary Fredericksen, Paolo Peterlongo, Bernard Peissel, Bernardo Bonanni, Alessandra Viel, Loris BernardPaolo Radice, Csilla I. Szabo, Lenka Foretova, Michal Zikan, Kathleen Claes, Mark H. Greene, Phuong L. Mai, Gad Rennert, Flavio Lejbkowicz, Irene L. Andrulis, Hilmi Ozcelik, Gord Glendon, Anne Marie Gerdes, Mads Thomassen, Lone Sunde, Maria A. Caligo, Yael Laitman, Tair Kontorovich, Shimrit Cohen, Bella Kaufman, Efrat Dagan, Ruth Gershoni Baruch, Eitan Friedman, Katja Harbst, Gisela Barbany-Bustinza, Johanna Rantala, Hans Ehrencrona, Per Karlsson, Susan M. Domchek, Katherine L. Nathanson, Ana Osorio, Ignacio Blanco, Adriana Lasa, Javier Benítez, Ute Hamann, Frans B.L. Hogervorst, Matti A. Rookus, J. Margriet Collee, Peter Devilee, Marjolijn J. Ligtenberg, Rob B. van der Luijt, Cora M. Aalfs, Quinten Waisfisz, Juul Wijnen, Cornelis E.P. van Roozendaal, Susan Peock, Margaret Cook, Debra Frost, Clare Oliver, Radka Platte, D. Gareth Evans, Fiona Lalloo, Rosalind Eeles, Louise Izatt, Rosemarie Davidson, Carol Chu, Diana Eccles, Trevor Cole, Shirley Hodgson, Andrew K. Godwin, Dominique Stoppa-Lyonnet, Bruno Buecher, Méanie Léoné, Brigitte Bressac-de Paillerets, Audrey Remenieras, Olivier Caron, Gilbert M. Lenoir, Nicolas Sevenet, Michel Longy, Sandra Fert Ferrer, Fabienne Prieur, David Goldgar, Alexander Miron, Esther M. John, Saundra S. Buys, Mary B. Daly, John L. Hopper, Mary Beth Terry, Yosuf Yassin, Christian Singer, Daphne Gschwantler-Kaulich, Christine Staudigl, Thomas V.O. Hansen, Rosa Bjork Barkardottir, Tomas Kirchhoff, Prodipto Pal, Kristi Kosarin, Kenneth Offit, Marion Piedmonte, Gustavo C. Rodriguez, Katie Wakeley, John F. Boggess, Jack Basil, Peter E. Schwartz, Stephanie V. Blank, Amanda E. Toland, Marco Montagna, Cinzia Casella, Evgeny N. Imyanitov, Anna Allavena, Rita K. Schmutzler, Beatrix Versmold, Christoph Engel, Alfons Meindl, Nina Ditsch, Norbert Arnold, Dieter Niederacher, Helmut Deißler, Britta Fiebig, Christian Suttner, Ines Schönbuchner, Dorothea Gadzicki, Trinidad Caldes, Miguel de la Hoya, Karen A. Pooley, Douglas F. Easton, Georgia Chenevix-Trench

Research output: Contribution to journalArticlepeer-review

Abstract

Genome-wide association studies of breast cancer have identified multiple single nucleotide polymorphisms (SNPs) that are associated with increased breast cancer risks in the general population. In a previous study, we demonstrated that the minor alleles at three of these SNPs, in FGFR2, TNRC9 and MAP3K1, also confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. Three additional SNPs rs3817198 at LSP1, rs13387042 at 2q35 and rs13281615 at 8q24 have since been reported to be associated with breast cancer in the general population, and in this study we evaluated their association with breast cancer risk in 9442 BRCA1 and 5665 BRCA2 mutation carriers from 33 study centres. The minor allele of rs3817198 was associated with increased breast cancer risk only for BRCA2 mutation carriers [hazard ratio (HR) = 1.16, 95% CI: 1.07-1.25, P-trend = 2.8 × 10-4]. The best fit for the association of SNP rs13387042 at 2q35 with breast cancer risk was a dominant model for both BRCA1 and BRCA2 mutation carriers (BRCA1: HR = 1.14, 95% CI: 1.04-1.25, P = 0.0047; BRCA2: HR = 1.18 95% CI: 1.04-1.33, P = 0.0079). SNP rs13281615 at 8q24 was not associated with breast cancer for either BRCA1 or BRCA2 mutation carriers, but the estimated association for BRCA2 mutation carriers (per-allele HR = 1.06, 95% CI: 0.98-1.14) was consistent with odds ratio estimates derived from population-based case-control studies. The LSP1 and 2q35 SNPs appear to interact multiplicatively on breast cancer risk for BRCA2 mutation carriers. There was no evidence that the associations vary by mutation type depending on whether the mutated protein is predicted to be stable or not.

Original languageEnglish
Pages (from-to)4442-4456
Number of pages15
JournalHuman Molecular Genetics
Volume18
Issue number22
DOIs
StatePublished - 15 Nov 2009
Externally publishedYes

Bibliographical note

Funding Information:
J.S., Francine Durocher, Rachel Laframboise, Marie Plante, Centre Hospitalier Universitaire de Quebec & Laval University, Quebec, Canada; Peter Bridge, Jilian Parboosingh, Molecular Diagnostic Laboratory, Alberta Children’s Hospital, Calgary, Canada; Jocelyne Chiquette, Hôpital du Saint-Sacrement, Quebec, Canada; Bernard Lesperance, Hôpital du Sacré-Cœur de Montréal, Montréal, Canada. J.S. is Chairholder of the Canada Research Chair in Oncogenetics. This work was supported by the Canadian Institutes of Health Research for the ‘CIHR Team in Familial Risks of Breast Cancer’ program.

Funding Information:
We wish to thank all the GEMO collaborating members (Cancer Genetics Network ‘Groupe Génétique et Cancer’, Fédération Nationale des Centres de Lutte Contre le Cancer, France) for their contribution to this study. We acknowledge the contribution of the Biobank of Institut de Cancérologie Gustave Roussy for providing their samples. The GEMO study was supported by the Ligue National Contre le Cancer and the Association ‘Le cancer du sein, parlons-en!’ Award. The GEMO study (Genetic Modifiers of cancer risk in BRCA1/2 mutation carriers) Collaborating Centers: Coordinating Centres, Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon/Centre Léon Bérard and UMR5201 CNRS, Université de Lyon, Lyon: O.M.S., Laure Barjhoux, Sophie Giraud, Mélanie Léone, Sylvie Mazoyer; and INSERM U509, Service de Génétique Oncologique, Institut Curie, Paris: D.S.-L., Marion Gauthier-Villars, Claude Houdayer, Virginie Moncoutier, Muriel Belotti, Antoine de Pauw. Institut Gustave Roussy, Villejuif: B.B.-d.-P., A.R., Véronique Byrde, Corinne Capoulade, G.M.L. Centre Jean Perrin, Clermont–Ferrand: Yves-Jean Bignon, Nancy Uhrhammer. Centre Léon Bérard, Lyon: Christine Lasset, Valérie Bonadona. Centre Franc¸ois Baclesse, Caen: Agnès Hardouin, Pascaline Berthet. Institut Paoli Calmettes, Marseille: Hagay Sobol, Violaine Bourdon, Franc¸ois 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, 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: M.L., N.S. Institut Claudius Regaud, Toulouse: Christine Toulas, Rosine Guimbaud, Laurence Gladieff, Viviane Feillel. CHU de Grenoble: Dominique Leroux, Hélène Dreyfus, Christine Rebischung. CHU de Dijon: Laurence Olivier-Faivre. CHU de St-Etienne: F.P. Centre Antoine Lacassagne, Nice: Marc Frénay. Creighton University, Omaha, USA: Henry T. Lynch.

Funding Information:
GC-HBOC is supported by a grant of the German Cancer Aid (grant107054) to R.K.S. We thank Juliane Köhler for her excellent technical assistance and the 14 centres of the GC-HBOC for providing samples and clinical data.

Funding Information:
This work was supported by the National Cancer Institute, National Institutes of Health under RFA-CA-06-503 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), 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 centres in the BCFR, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the BCFR.

Funding Information:
This work was supported by NIH grant R01-CA74415 (to S.L.N.).

Funding Information:
The study was supported by the Ministero dell’Università e della Ricerca (MIUR), Ministero della Sanità and Alleanza Contro il Cancro.

Funding Information:
This work was supported 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.

Funding Information:
The research of M.H.G. and P.L.M. 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 was performed by NCI’s Core Genotyping Facility, Gaithersburg, MD.

Funding Information:
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, Siranoush Manoukian, 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 and Laura Tizzoni of the Cogentech, Consortium for Genomic Technologies, Milan, Italy.

Funding Information:
We acknowledge support from the Breast Cancer Research Foundation, the Starr Foundation and the Niehaus Cancer Research Initiative.

Funding Information:
C.I.S. 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 Research Project of the Ministry of Education, Youth, and Sports of the Czech Republic grant MSM0021620808 (to M.Z., Zdenek Kleibl and Petr Pohlreich). L.F., Machakova Eva and Lukesova Miroslava’s are supported through the Ministry of Health grant CR-MZ0 MOU 2005. We acknowledge the contribution of Kim De Leeneer, Bruce Poppe, 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).

Funding Information:
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.

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

Funding Information:
This work was partially supported by research grants to EF from the Tel Aviv University and the Israel cancer association.

Funding Information:
This work is supported by the Neye Foundation.

Funding Information:
Thanks to Rosario Alonso, Alicia Barroso, Guillermo Pita and Roger Milne for their support. The samples studied at CNIO were recruited through centres participating in the Spanish Consortium for the Study of Genetic Modifiers of BRCA1 and BRCA2: Spanish National Cancer Centre (Madrid), Catalan Institute of Oncology (Barcelona), Sant Pau Hospital (Barcelona), Dexeus Institute (Barcelona) and Demokritos Institute (Athens, Greece). The work carried out at CNIO was partly funded by FIS 081120 and Asociación Española Contra el Cáncer (AECC) grants.

Funding Information:
Coordinating Center: Netherlands Cancer Institute, Amsterdam: F.B.L.H., Senno Verhoef, Anouk Pijpe, Laura van ‘t Veer, Flora van Leeuwen, M.A.R.; Erasmus Medical Center, Rotterdam: J.M.C., Ans van den Ouweland, Mieke Kriege, Mieke Schutte, Maartje Hooning, Caroline Seynaeve; Leiden University Medical Center, Leiden: Rob Tollenaar, Christi van Asperen, J.W., Maaike Vreeswijk, P.D.; Radboud University Nijmegen Medical Center, Nijmegen: Nicoline Hoogerbrugge, M.J.L.; University Medical Center Utrecht, Utrecht: Margreet Ausems, R.v.d.L.; Amsterdam Medical Center: C.M.A., Theo van Os; VU University Medical Center, Amsterdam: Hanne Meijers-Heijboer, Hans Gille; University Hospital Maastricht, Maastricht: Encarna Gomez-Garcia, Rien Blok. The HEBON study is supported by the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI 2007-3756.

Funding Information:
This work was supported in part by grants from the Breast Cancer Research Foundation (BCRF), the Komen Foundation and the National Cancer Institute, NIH (CA128978 and CA122340). The authors thank Mary Karaus for co-ordination or recruitment of carriers to the MAYO study.

Funding Information:
DFE is the PI of the study. EMBRACE Collaborating Centers are: Coordinating Centre, Cambridge: S.P., M.C., C.O., D.F. North of Scotland Regional Genetics Service, Aberdeen: Zosia Miedzybrodzka, Helen Gregory. Northern Ireland Regional Genetics Service, Belfast: Patrick Morrison. West Midlands Regional Clinical Genetics Service, Birmingham: T.C., Carole McKeown, Lucy Burgess. 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: R.D., Victoria Murday, Nicola Bradshaw, Lesley Snadden, Mark Longmuir, Catherine Watt. South East Thames Regional Genetics Service, Guys Hospital London: L.I., 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: C.C., Tim Bishop, Julie Miller. Merseyside & Cheshire Clinical Genetics Service, Liverpool: Ian Ellis. Manchester Regional Genetics Service, Manchester: D.G.E., F.L., Felicity Holt. D.G.E. and F.L. are supported the NIHR Biomedical research centre, Manchester. 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. Oxford Regional Genetics Service, Oxford: Lisa Walker, Sarah Durell. 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: S.H., Sheila Goff, Glen Brice, Lizzie Winchester. Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton: Gillian Crawford, Emma Tyler, Donna McBride, Anneke Lucassen. S.P., M.C., D.F., C.O. and R.P. 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.

Funding Information:
The HEBCS thanks Drs Kristiina Aittomäki, Kirsimari Aaltonen and Carl Blomqvist and RN Hanna Jäntti for their help with the patient data and gratefully acknowledges the Finnish Cancer Registry for the cancer 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.

Funding Information:
This study was supported by National Cancer Institute grants to the Gynecologic Oncology Group Administrative Office (CA 27469) and the Gynecologic Oncology Group Statistical and Data Center (CA 37517). Genotyping of GOG DNA samples was performed by NCI’s Core Genotyping Facility. The technical expertise of Tim Sheehy, and Amy Hutchinson is gratefully acknowledged.

Funding Information:
The work of A.A. has been supported by Compagnia di San Paolo (Progetto Oncologia).

Funding Information:
Supported by RFBR grants 08-04-00369 and 09-04-90402.

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics
  • Molecular Biology

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