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

Human molecular genetics ·Vol. 20 ·No. 23 ·2012-02-22

Cox David G, Simard Jacques, Sinnett Daniel, Hamdi Yosr, Soucy Penny, Ouimet Manon, Barjhoux Laure, Verny-Pierre Carole, McGuffog Lesley, Healey Sue, Szabo Csilla, Greene Mark H, Mai Phuong L, Andrulis Irene L, , Thomassen Mads, Gerdes Anne-Marie, Caligo Maria A, Friedman Eitan, Laitman Yael, Kaufman Bella, Paluch Shani S, Borg Åke, Karlsson Per, Askmalm Marie Stenmark, Bustinza Gisela Barbany, , Nathanson Katherine L, Domchek Susan M, Rebbeck Timothy R, Benítez Javier, Hamann Ute, Rookus Matti A, van den Ouweland Ans M W, Ausems Margreet G E M, Aalfs Cora M, van Asperen Christi J, Devilee Peter, Gille Hans J J P, , , Peock Susan, Frost Debra, Evans D Gareth, Eeles Ros, Izatt Louise, Adlard Julian, Paterson Joan, Eason Jacqueline, Godwin Andrew K, Remon Marie-Alice, Moncoutier Virginie, Gauthier-Villars Marion, Lasset Christine, Giraud Sophie, Hardouin Agnès, Berthet Pascaline, Sobol Hagay, Eisinger François, Bressac de Paillerets Brigitte, Caron Olivier, Delnatte Capucine, , Goldgar David, Miron Alex, Ozcelik Hilmi, Buys Saundra, Southey Melissa C, Terry Mary Beth, , Singer Christian F, Dressler Anne-Catharina, Tea Muy-Kheng, Hansen Thomas V O, Johannsson Oskar, Piedmonte Marion, Rodriguez Gustavo C, Basil Jack B, Blank Stephanie, Toland Amanda E, Montagna Marco, Isaacs Claudine, Blanco Ignacio, Gayther Simon A, Moysich Kirsten B, Schmutzler Rita K, Wappenschmidt Barbara, Engel Christoph, Meindl Alfons, Ditsch Nina, Arnold Norbert, Niederacher Dieter, Sutter Christian, Gadzicki Dorothea, Fiebig Britta, Caldes Trinidad, Laframboise Rachel, Nevanlinna Heli, Chen Xiaoqing, Beesley Jonathan, Spurdle Amanda B, Neuhausen Susan L, Ding Yuan C, Couch Fergus J, Wang Xianshu, Peterlongo Paolo, Manoukian Siranoush, Bernard Loris, Radice Paolo, Easton Douglas F, Chenevix-Trench Georgia, Antoniou Antonis C, Stoppa-Lyonnet Dominique, Mazoyer Sylvie, Sinilnikova Olga M,

Abstract

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.

Article Info

Journal

Human molecular genetics

Abbr.

Hum Mol Genet

ISSN

0964-6906

Published

2012-02-22

Indexed

2011-11-08

Updated

2016-12-03

Language

English

Country/Region

England

NLM ID

9208958

External Links

PubMed source View journal details

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

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