BRCA1 Wild-Type Allele Modifies Risk of Ovarian Cancer in Carriers of BRCA1 Germ-Line Mutations

BRCA1 Wild-Type Allele Modifies Risk of Ovarian Cancer in Carriers of BRCA1 Germ-Line Mutations1

Centre National de la Recherche Scientifique, UMR 5641, Lyon, France [S. M. G., S. M.]; Centre International de Recherche sur le Cancer, Lyon, France [S. M. G., M. C., C. S., D. G., G. M. L., O. M. S.]; Institut National de la, France Santé et de la Recherche Médicale (INSERM) U509, Service de Génétique Oncologique, Institut Curie, Paris, France [S. Ga., D. S-L.]; Institut Gustave Roussy, Villejuif, France [B. B-d-P., A. C.]; Centre Jean Perrin, Clermont-Ferrand, France [Y-J. B.]; Centre Oscar Lambret, Lille, France [J-P. P., J. F.]; Centre Léon Bérard, Lyon, France [C. L.]; Hospices Civils de Lyon, Lyon, France [S. Gi., O. M. S.]; Centre Paul Strauss, Strasbourg, France [D. M., J-P. F.]; Centre François Baclesse, Caen, France [A. H., P. B.]; Centre René Gauducheau, Nantes, France [C. M.]; Centre René Huguenin, St. Cloud, France [C. N., R. L.]; Institut Bergonié, Bordeaux, France [M. L.]; Centre d’Etudes Polymorphisme des Humains, Paris, France [S. O.]; Institut Claudius Regaud, Toulouse, France [C. T., R. G.]; National Center for Scientific Research Demokritos, Athens, Greece [D. Y.]; Centre Hospitalo Universitaire Laval, Quebec, Canada [F. D., A-M. M., J. S.]; Consortium Interdisciplinary Health Research International Team on Breast Cancer Susceptibility (INHERIT BRCAs) [F. D., A-M. M., J. S.]; and Creighton University, Omaha, Nebraska [H. T. L.]

Abstract

Strong inter- and intrafamilial variation of penetrance of breast and ovarian cancer is observed in BRCA1 mutation carriers. The wild-type copy of the BRCA1 gene is a plausible candidate as a cancer risk modifier given that the residual function corresponding to the intact BRCA1 allele may influence the process of tumor formation in BRCA1 carriers. Indeed, growing evidence is now becoming available on impaired reparation of double-strand DNA breaks in cells heterozygous for BRCA1 mutations, implying an enhanced mutability of BRCA1^+/− cells. To determine whether certain variant forms of the wild-type BRCA1 allele are implicated in variation of the BRCA1-related cancer risk, their effect was studied in a panel of 591 women with BRCA1 germ-line mutations. We found that BRCA1 carriers with the wild-type BRCA1 copy bearing a common Gly1038 variant were at increased risk of ovarian cancer (hazards ratio, 1.50; 95% confidence interval, 1.03–2.19). The results of our study imply that a quite significant proportion of the interindividual variability in ovarian cancer penetrance in BRCA1 carriers may be explained by a common BRCA1 Gly1038 wild-type allele, given its high frequency (0.27).

Footnotes

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↵1 Supported by the Programme Hospitalier de Recherche Clinique AOR01082, Programme Incitatif et Coopératif: Génétique et Biologie de Cancer du Sein, Institut Curie, Paris. The INHERIT BRCAs program is funded by the Canadian Institutes of Health Research. S. M. G. and S. Ga. are the recipients of fellowships from the Association pour la Recherche sur le Cancer, France. F. D. is a Hitchings-Elion fellow from the Burroughs Wellcome Fund. J. S. is chairholder of the Canada Research Chair in Oncogenetics.
↵2 Present address: Institut Gustave Roussy, 94805 Villejuif, France.
↵3 To whom requests for reprints should be addressed, at the Unit of Genetic Epidemiology, International Agency for Research on Cancer, 150, cours Albert Thomas, F 69372 Lyon Cedex 08, France. Phone: 33-4-72-73-83-15; Fax: 33-4-72-73-83-42; E-mail: sinilnikova{at}iarc.fr
↵4 The abbreviations used are: SNP, single nucleotide polymorphism; HR, hazards ratio; CI, confidence interval.
- Accepted November 27, 1902.
- Received July 29, 1902.
- Revision received November 20, 1902.