Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers

• DOI: 10.1093/hmg/ddr388
• Publication Date: 2011-09-03T00:51:14Z
• Authors: David G. Cox; Jacques Simard; Daniel Sinnett; Yosr Hamdi; Penny Soucy; Manon Ouimet; Laure Barjhoux; Carole Verny-Pierre; Lesley McGuffog; Sue Healey; Csilla Szabo; Mark H. Greene; Phuong L. Mai; Irene L. Andrulis; ; Mads Thomassen; Anne-Marie Gerdes; Maria A. Caligo; Eitan Friedman; Yael Laitman; Bella Kaufman; Shani S. Paluch; Åke Borg; Per Karlsson; Marie Stenmark As...; Gisela Barbany Bu...; ; Katherine L. Nath...; Susan M. Domchek; Timothy R. Rebbeck; Javier Benítez; Ute Hamann; Matti A. Rookus; Ans M.W. van den ...; Margreet G.E.M. A...; Cora M. Aalfs; Christi J. van As...; Peter Devilee; Hans J.J.P. Gille; ; ; Susan Peock; Debra Frost; D. Gareth Evans; Ros Eeles; Louise Izatt; Julian Adlard; Joan Paterson; Jacqueline Eason; Andrew K. Godwin; Marie-Alice Remon; Virginie Moncoutier; Marion Gauthier-V...; Christine Lasset; Sophie Giraud; Agnès Hardouin; Pascaline Berthet; Hagay Sobol; François Eisinger; Brigitte Bressac ...; Olivier Caron; Capucine Delnatte; ; David Goldgar; Alex Miron; Hilmi Ozcelik; Saundra Buys; Melissa C. Southey; Mary Beth Terry; ; Christian F. Singer; Anne-Catharina Dr...; Muy-Kheng Tea; Thomas V.O. Hansen; Oskar Johannsson; Marion Piedmonte; Gustavo C. Rodriguez; Jack B. Basil; Stephanie Blank; Amanda E. Toland; Marco Montagna; Claudine Isaacs; Ignacio Blanco; Simon A. Gayther; Kirsten B. Moysich; Rita K. Schmutzler; Barbara Wappensch...; Christoph Engel; Alfons Meindl; Nina Ditsch; Norbert Arnold; Dieter Niederacher; Christian Sutter; Dorothea Gadzicki; Britta Fiebig; Trinidad Caldes; Rachel Laframboise; Heli Nevanlinna; Xiaoqing Chen; Jonathan Beesley; Amanda B. Spurdle; Susan L. Neuhausen; Yuan C. Ding; Fergus J. Couch; Xianshu Wang; Paolo Peterlongo; Siranoush Manoukian; Loris Bernard; Paolo Radice; Douglas F. Easton; Georgia Chenevix-...; Antonis C. Antoniou; Dominique Stoppa-...; Sylvie Mazoyer; Olga M. Sinilnikova; ; Martine Dumont; P.L. Mai; MH Greene; Gord Glendon; Teresa Selander; Nayana Weerasooriya; Per Karlsson; Margareta Nordling; Annika Bergman; Zakaria Einbeigi; Marie Stenmark-As...; Sigrun Liedgren; Åke Borg; Niklas Loman; Håkan Olsson; Ulf Kristoffersson; Maria Soller; Helena Jernström; Katja Harbst; Karin Henriksson; Annika Lindblom; Brita Arver; Anna von Wachenfeldt; Annelie Liljegren; Gisela Barbany-Bu...; Johanna Rantala; Beatrice Melin; Henrik Grönberg; Eva-Lena Stattin; Monica Emanuelsson; Hans Ehrencrona; Diana Torres; Muhammad U. Rashid; Antje Seidel-Renkert; F.B.L. Hogervorst; S. Verhoef; M. Verheus; L.J. van't Veer; F.E. van Leeuwen; M.A. Rookus; M. Collée; A.M.W. van den Ou...; A. Jager; M.J. Hooning; M.M.A. Tilanus-Li...; C. Seynaeve; C.J. van Asperen; J.T. Wijnen; M.P. Vreeswijk; R.A. Tollenaar; P. Devilee; M.J. Ligtenberg; N. Hoogerbrugge; M.G. Ausems; R.B. van der Luijt; C.M. Aalfs; T.A. van Os; J.J.P. Gille; Q. Waisfisz; H.E.J. Meijers-He...; E.B. Gomez-Garcia; C.E. van Roozendaal; Marinus J. Blok; B. Caanen; J.C. Oosterwijk; A.H. van der Hout; M.J. Mourits; H.F. Vasen; Douglas F. Easton; Susan Peock; Margaret Cook; Debra Frost; Radka Platte; Zosia Miedzybrodzka; Helen Gregory; Patrick Morrison; Lisa Jeffers; Trevor Cole; Kai-ren Ong; Jonathan Hoffman; Alan Donaldson; Margaret James; Joan Paterson; Sarah Downing; Amy Taylor; Alexandra Murray; Mark T. Rogers; Emma McCann; M. John Kennedy; David Barton; Mary Porteous; Sarah Drummond; Carole Brewer; Emma Kivuva; Anne Searle; Selina Goodman; Kathryn Hill; Rosemarie Davidson; Victoria Murday; Nicola Bradshaw; Lesley Snadden; Mark Longmuir; Catherine Watt; Sarah Gibson; Eshika Haque; Ed Tobias; Alexis Duncan; Louise Izatt; Chris Jacobs; Caroline Langman; Anna Whaite; Huw Dorkins; Julian Barwell; Julian Adlard; Carol Chu; Julie Miller; Ian Ellis; Catherine Houghton; D. Gareth Evans; Fiona Lalloo; Jane Taylor; Lucy Side; Alison Male; Cheryl Berlin; Jacqueline Eason; Rebecca Collier; Fiona Douglas; Oonagh Claber; Irene Jobson; Lisa Walker; Diane McLeod; Dorothy Halliday; Sarah Durell; Barbara Stayner; Ros Eeles; Susan Shanley; Nazneen Rahman; Richard Houlston; Elizabeth Bancroft; Lucia D'Mello; Elizabeth Page; Audrey Ardern-Jones; Kelly Kohut; Jennifer Wiggins; Elena Castro; Anita Mitra; Lisa Robertson; Jackie Cook; Oliver Quarrell; Cathryn Bardsley; Shirley Hodgson; Sheila Goff; Glen Brice; Lizzie Winchester; Charlotte Eddy; Vishakha Tripathi; Virginia Attard; Diana Eccles; Anneke Lucassen; Gillian Crawford; Donna McBride; Sarah Smalley; D. Gareth Evans; Fiona Lalloo; Ros Eeles; Elizabeth Bancroft; Lucia D'Mello; Olga Sinilnikova; Laure Barjhoux; Carole Verny-Pierre; Sophie Giraud; Mélanie Léone; Sylvie Mazoyer; Dominique Stoppa-...; Marion Gauthier-V...; Bruno Buecher; Claude Houdayer; Virginie Moncoutier; Muriel Belotti; Carole Tirapo; Antoine de Pauw; Brigitte Bressac-...; Audrey Remenieras; Véronique Byrde; Olivier Caron; Gilbert Lenoir; Yves-Jean Bignon; Nancy Uhrhammer; Christine Lasset; Valérie Bonadona; Agnès Hardouin; Pascaline Berthet; Hagay Sobol; Violaine Bourdon; Tetsuro Noguchi; François Eisinger; Florence Coulet; Chrystelle Colas; Florent Soubrier; Isabelle Coupier; Pascal Pujol; Jean-Philippe Peyrat; Joëlle Fournier; Françoise Révillion; Philippe Vennin; Claude Adenis; Etienne Rouleau; Rosette Lidereau; Liliane Demange; Catherine Nogues; Danièle Muller; Jean-Pierre Fricker; Michel Longy; Nicolas Sevenet; Christine Toulas; Rosine Guimbaud; Laurence Gladieff; Viviane Feillel; Dominique Leroux; Hélène Dreyfus; Christine Rebischung; Fanny Coron; Laurence Faivre; Fabienne Prieur; Marine Lebrun; Sandra Fert Ferrer; Marc Frénay; Laurence Vénat-Bo...; Capucine Delnatte; Isabelle Mortemou...; Henry T. Lynch; Carrie L. Snyder; Bent Ejlertsen; Mette K. Andersen; Susanne Kjaergaard; Leigha Senter; Kevin Sweet; Michelle O'Connor; Caroline Craven; Paul Pharoah; Susan Ramus; Carole Pye; Patricia Harrington; Eva Wozniak; Raymonda Varon-Ma...; Karin Kast; Sabine Preisler-A...; Helmut Deissler; Ines Schönbuchner; Wolfram Heinritz; Dieter Schäfer; Kristiina Aittomäki; Carl Blomqvist; Tuomas Heikkinen; R.N. Irja Erkkilä; Heather Thorne; Eveline Niedermayr; Miguel de la Hoya; Pedro Perez-Segura
• Keywords: Electrophoretic Mobility Shift Assay; Linkage Disequilibrium; 0302 clinical medicine; MESH: Risk Factors; ONCOL 1: Hereditary cancer and cancer-related syndromes; Genes, Reporter; Risk Factors; Luciferases; EMC MGC-02-96-01; MESH: Genetic Association Studies; MESH: Heterozygote; ddc:610; BRCA1 Protein; MESH: Polymorphism, Single Nucleotide; MESH: Genetic Predisposition to Disease; Single Nucleotide; MESH: Genes; 3. Good health; MESH: Linkage Disequilibrium; Female; Heterozygote; MESH: Mutation; 610; [SDV.CAN]Life Sciences [q-bio]/Cancer; Breast Neoplasms; Polymorphism, Single Nucleotide; 03 medical and health sciences; [SDV.CAN] Life Sciences [q-bio]/Cancer; SDG 3 - Good Health and Well-being; Humans; Genetic Predisposition to Disease; Reporter; MESH: Polymorphism; Alleles; Genetic Association Studies; MESH: BRCA1 Protein; MESH: Humans; MESH: Alleles; MESH: Genes, Reporter; MESH: Haplotypes; Haplotypes; MESH: Electrophoretic Mobility Shift Assay; MESH: HeLa Cells; Mutation; MESH: Luciferases; MESH: Female; MESH: Breast Neoplasms; HeLa Cells

Mutations in the BRCA1 gene substantially increase a woman's lifetime risk of breast cancer. However, there is great variation in this increase in risk with several genetic and non-genetic modifiers identified. The BRCA1 protein plays a central role in DNA repair, a mechanism that is particularly instrumental in safeguarding cells against tumorigenesis. We hypothesized that polymorphisms that alter the expression and/or function of BRCA1 carried on the wild-type (non-mutated) copy of the BRCA1 gene would modify the risk of breast cancer in carriers of BRCA1 mutations. A total of 9874 BRCA1 mutation carriers were available in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) for haplotype analyses of BRCA1. Women carrying the rare allele of single nucleotide polymorphism rs16942 on the wild-type copy of BRCA1 were at decreased risk of breast cancer (hazard ratio 0.86, 95% confidence interval 0.77-0.95, P = 0.003). Promoter in vitro assays of the major BRCA1 haplotypes showed that common polymorphisms in the regulatory region alter its activity and that this effect may be attributed to the differential binding affinity of nuclear proteins. In conclusion, variants on the wild-type copy of BRCA1 modify risk of breast cancer among carriers of BRCA1 mutations, possibly by altering the efficiency of BRCA1 transcription.