No association of TGFB1 L10P genotypes and breast cancer risk in BRCA1 and BRCA2 mutation carriers: a multi-center cohort study
- 70 Downloads
Background The transforming growth factor β-1 gene (TGFB1) is a plausible candidate for breast cancer susceptibility. The L10P variant of TGFB1 is associated with higher circulating levels and secretion of TGF-β, and recent large-scale studies suggest strongly that this variant is associated with breast cancer risk in the general population. Methods To evaluate whether TGFB1 L10P also modifies the risk of breast cancer in BRCA1 or BRCA2 mutation carriers, we undertook a multi-center study of 3,442 BRCA1 and 2,095 BRCA2 mutation carriers. Results We found no evidence of association between TGFB1 L10P and breast cancer risk in either BRCA1 or BRCA2 mutation carriers. The per-allele HR for the L10P variant was 1.01 (95%CI: 0.92–1.11) in BRCA1 carriers and 0.92 (95%CI: 0.81–1.04) in BRCA2 mutation carriers. Conclusions These results do not support the hypothesis that TGFB1 L10P genotypes modify the risk of breast cancer in BRCA1 or BRCA2 mutation carriers.
KeywordsBRCA1 BRCA2 Risk modifiers Hereditary cancer
Consortium of Investigators of Modifiers of BRCA1/2
Breast Cancer Association Consortium
Breast Cancer Family Registries
Epidemiological Study of Familial Breast Cancer
German Consortium of Hereditary Breast and Ovarian Cancer
Helsinki Breast Cancer Study
Hospital Clinico San Carlos
Interdisciplinary Health Research International Team Breast Cancer Susceptibility
The Kathleen Cunningham Consortium for Research into Familial Breast Cancer
Modifier study of quantitative effects on disease
National Cancer Institute Study
Ontario Cancer Genetics Network Study
Genetic Modifiers of cancer risk in BRCA1/2 mutation carriers study
Transforming growth factor-β
ACA, HAP and the CIMBA data management are funded by Cancer Research––UK. Douglas F. Easton is a Principal Research Fellow of Cancer Research––UK. Timothy R. Rebbeck is supported by R01-CA102776. Boris Pasche is supported by R01-CA112520.
Timothy R. Rebbeck, Douglas E. Easton, Antonis C. Antoniou, Amanda B. Spurdle, Georgia Chenevix-Trench, Boris Pasche, Virginia Kaklamani, Fergus J. Couch made substantial contributions to conception and design. Antonis C. Antoniou, Susan Peock, Margaret Cook, Douglas E. Easton, Jean-Philippe Peyrat, Joëlle Fournier, Philippe Vennin, Claude Adenis, Danièle Muller, Jean-Pierre Fricker, Michel Longy, Olga M. Sinilnikova, Dominique Stoppa-Lyonnet, Ute Hamann, Amanda B. Spurdle, Georgia Chenevix-Trench, Patricia A. Harrington, Alan Donaldson, Allison M. Male, Carol Anne Gardiner, Heli Nevanlinna, Helen Gregory, Lucy E. Side, Anne C. Robinson, Louise Emmerson, Ian Ellis, Boris Pasche, Virginia Kaklamani, Rita K. Schmutzler, Beatrix Versmold, Christoph Engel, Alfons Meindl, Karin Kast, Dieter Schaefer, Ursula G. Froster, Trinidad Caldes Llopis, Kristiina Aittomäki, Fergus J. Couch, Jacques Simard, Lutecia H. Mateus Pereira, Mark H. Greene, Irene L. Andrulis made substantial contributions to acquisition of data. Timothy R. Rebbeck, Antonis C. Antoniou, Douglas E. Easton, made substantial contributions to analysis and interpretation of data. Timothy R. Rebbeck, Antonis C. Antoniou, Douglas E. Easton, Georgia Chenevix-Trench, Boris Pasche, Jacques Simard, Irene L. Andrulis were involved in drafting the manuscript or revising it critically for important intellectual content. All authors have given final approval of the version to be published.
Participating CIMBA centres
Breast Cancer Family Registry (BCFR)
BCFR was supported by the National Cancer Institute, National Institutes of Health under RFA # CA-95-011 and through cooperative agreements with members of the BCFR, including Cancer Care Ontario (U01 CA69467, PI: Irene A. Andrulis), Columbia University (U01 CA69398, PI: Mary Beth Terry), Fox Chase Cancer Center (U01 CA69631, PI: Mary Daly), Huntsman Cancer Institute (U01 CA69446, PI: Saundra Buys), Northern California Cancer Center (U01 CA69417, PI: Esther M. John), University of Melbourne (U01 CA69638, PI: John L. Hopper), 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 CFR, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the CFR.
German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC)
GC-HBOC is supported by a grant of the German Cancer Aid (grant107054) and the Center for Molecular Medicine Cologne (grant TV93) to Rita K. Schmutzler. We thank Juliane Köhler for her excellent technical assistance and the 12 centers of the GC-HBOC for providing samples and clinical data.
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 and Kati Kämpjärvi for their contribution in the molecular analyses and Drs. Kirsimari Aaltonen and Carl Blomqvist, for their help in patient sample and data collection.
Hospital Clinico San Carlos (HCSC)
Trinidad Caldes is funded by FMMA/06 and RTICC06/002/0021 HCSC-Spain. We thank Miguel de la Hoya, Pedro Perez-Segura and Elena Oliveira for their contribution.
Interdisciplinary Health Research International Team Breast Cancer susceptibility (INHERIT)
Jacques Simard, Francine Durocher, Rachel Laframboise, Marie Plante, Centre Hospitalier Universitaire de Québec & Laval University, Québec, Canada; Peter Bridge, Jilian Parboosingh, Molecular Diagnostic Laboratory, Alberta Children’s Hospital, Calgary, Canada; Jocelyne Chiquette, Hôpital du Saint-Sacrement, Québec, Canada; Bernard Lesperance, Roxanne Pichette, Hôpital du Sacré-Cœur de Montréal, Montréal, 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 Cunningham Consortium for Research into Familial Breast Cancer (KConFab)
We wish to thank Heather Thorne, Eveline Niedermayr, Helene Holland, Xiaoqing Chen and Jonathan Beesley, 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 and its management, and the many families who contribute to KConFab. KConFab is supported by grants from the National Breast Cancer Foundation, the National Health and Medical Research Council (NHMRC) and by the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. Amanda B. Spurdle and Georgia Chenevix-Trench are NHMRC Career Development Awardee and Senior Principal Research Fellow, respectively.
Mayo Clinic Study (MAYO)
The Mayo Clinic study was supported by the 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 Fergus J Couch. We wish to thank Noralane Lindor and Linda Wadum for their contributions.
Modifier Study of Quantitative Effects on Disease (Mod-Squad)
Csilla I. Szabo 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 Lukesova Miroslava (Department of Cancer).
National Cancer Institute study (NCI)
We acknowledge the contributions of Dr. Jeffery Struewing and Marbin A. Pineda from the Laboratory of Population Genetics. Drs. Greene and Struewing were supported by funding from the Intramural Research Program of the US National Cancer Institute. Their data collection efforts were supported by Contracts NO2-CP-11019-50 and N02-CP-65504 with Westat, Rockville, MD.
Ontario Cancer Genetics Network study (OCGN)
We thank the staff and all of those who participate in the OCGN. We acknowledge the contributions of the provincial familial cancer clinics and molecular diagnostic laboratories and Mona Gill for excellent technical assistance. The OCGN study was supported by funding from Cancer Care Ontario and the National Cancer Institute of Canada with funds from the Terry Fox Run.
Deutsches Krebsforschungszentrum study (DKFZ)
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.
Epidemiological study of BRCA1 & BRCA2 mutation carriers (EMBRACE)
Margaret Cook, Susan Peock and EMBRACE are funded by Cancer Research–UK. DFE is the PI of the study. EMBRACE Collaborating Centers are: Coordinating Centre, Cambridge: Susan Peock, Margaret Cook, 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, 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, Mark Rogers. St James’s Hospital, Dublin & National Centre for Medical Genetics, Dublin: Peter Daly, David Barton. South East of Scotland Regional Genetics Service, Edinburgh: Mary Porteous, Michael Steel. Peninsula Clinical Genetics Service. Exeter: Carole Brewer, Julia Rankin. West of Scotland Regional Genetics Service, Glasgow: Rosemarie Davidson, Victoria Murday. South East Thames Regional Genetics Service, Guys Hospital London: Louise Izatt, 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, Carol Chu. Merseyside & Cheshire Clinical Genetics Service. Liverpool: Ian Ellis. Manchester Regional Genetics Service, Manchester: D Gareth Evans, Fiona Lalloo, Andrew Shenton. North East Thames Regional Genetics Service, NE Thames: Alison Male, James Mackay, Anne Robinson. Nottingham Clinical Genetics service, Nottingham University Hospitals, Nottingham: Carol Gardiner. Northern Clinical Genetics Service, Newcastle: Fiona Douglas, John Burn. Oxford Regional Genetics Service, Oxford: Lucy Side, Lucy Walker, Sarah Durell. Institute of Cancer Research and Royal Marsden NHS Foundation Trust: Rosalind Eeles. North Trent Clinical Genetics Service, Sheffield: Jackie Cook, Oliver Quarrell. South West Thames Regional Genetics Service, London: Shirley Hodgson. Wessex Clinical Genetics Service. Southampton: Diana Eccles, Anneke Lucassen.
Genetic Modifiers of cancer risk in BRCA1/2 mutation carriers study (GEMO)
We wish to thank Laure Barjhoux for management the GEMO samples and carrying out genotyping, and all the GEMO centers for their contributions to this resource. 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.
- 3.Ziv E, Cauley J, Morin PA, Saiz R, Browner WS (2001) Association between the T29→C polymorphism in the transforming growth factor beta1 gene and breast cancer among elderly white women: the study of osteoporotic fractures. JAMA 285(22):2859–2863. doi: 10.1001/jama.285.22.2859 PubMedCrossRefGoogle Scholar
- 7.Jin Q, Hemminki K, Grzybowska E, Klaes R, Soderberg M, Zientek H et al (2004) Polymorphisms and haplotype structures in genes for transforming growth factor beta1 and its receptors in familial and unselected breast cancers. Int J Cancer 112(1):94–99. doi: 10.1002/ijc.20370 PubMedCrossRefGoogle Scholar
- 18.Chenevix-Trench G, Milne RL, Antoniou AC, Couch FJ, Easton DF, Goldgar DE (2007) An international initiative to identify genetic modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers: the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA). Breast Cancer Res 9(2):104. doi: 10.1186/bcr1670 PubMedCrossRefGoogle Scholar
- 19.Antoniou A, Pharoah PD, Narod S, Risch HA, Eyfjord JE, Hopper JL et al (2003) Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 72(5):1117–1130. doi: 10.1086/375033 PubMedCrossRefGoogle Scholar
- 20.Antoniou A, Sinilnikova O, Simard J, Léoné M, Dumont M, Neuhausen S, Struewing JLD, Barjhoux L, Hughes D, Coupier I et al (2007) RAD51 135G>C modifies breast cancer risk among BRCA2 mutation carriers: results from a combined analysis of 19 studies. Am J Hum Genet 81:1186–1200Google Scholar
- 22.Lin DY, Wei LJ (1989) The robust inference for the Cox proportional hazards model. JASA 84:1074–1078Google Scholar
- 23.Huber PJ (1967) The behavior of maximum likelihood estimates under non-standard conditions. Proc Fifth Berkley Symp Math Stat Probab 1:221–233Google Scholar
- 26.Lakhani SR, Van De Vijver MJ, Jacquemier J, Anderson TJ, Osin PP, McGuffog L et al (2002) The pathology of familial breast cancer: predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2. J Clin Oncol 20(9):2310–2318. doi: 10.1200/JCO.2002.09.023 PubMedCrossRefGoogle Scholar
- 27.Bane AL, Beck JC, Bleiweiss I, Buys SS, Catalano E, Daly MB et al (2007) BRCA2 mutation-associated breast cancers exhibit a distinguishing phenotype based on morphology and molecular profiles from tissue microarrays. Am J Surg Pathol 31(1):121–128. doi: 10.1097/01.pas.0000213351.49767.0f PubMedCrossRefGoogle Scholar