Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers
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Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers. / 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 W.; 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; Ontario Cancer Genetics Network.
I: Human Molecular Genetics, Bind 20, Nr. 23, 2011, s. 4732-47.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers
AU - Cox, David G
AU - Simard, Jacques
AU - Sinnett, Daniel
AU - Hamdi, Yosr
AU - Soucy, Penny
AU - Ouimet, Manon
AU - Barjhoux, Laure
AU - Verny-Pierre, Carole
AU - McGuffog, Lesley
AU - Healey, Sue
AU - Szabo, Csilla
AU - Greene, Mark H
AU - Mai, Phuong L
AU - Andrulis, Irene L
AU - Thomassen, Mads
AU - Gerdes, Anne-Marie
AU - Caligo, Maria A
AU - Friedman, Eitan
AU - Laitman, Yael
AU - Kaufman, Bella
AU - Paluch, Shani S
AU - Borg, Åke
AU - Karlsson, Per W.
AU - Askmalm, Marie Stenmark
AU - Bustinza, Gisela Barbany
AU - Nathanson, Katherine L
AU - Domchek, Susan M
AU - Rebbeck, Timothy R
AU - Benítez, Javier
AU - Hamann, Ute
AU - Rookus, Matti A
AU - van den Ouweland, Ans M W
AU - Ausems, Margreet G E M
AU - Aalfs, Cora M
AU - van Asperen, Christi J
AU - Devilee, Peter
AU - Gille, Hans J J P
AU - Peock, Susan
AU - Frost, Debra
AU - Evans, D Gareth
AU - Eeles, Ros
AU - Izatt, Louise
AU - Adlard, Julian
AU - Paterson, Joan
AU - Eason, Jacqueline
AU - Godwin, Andrew K
AU - Remon, Marie-Alice
AU - Moncoutier, Virginie
AU - Gauthier-Villars, Marion
AU - Lasset, Christine
AU - Ontario Cancer Genetics Network
PY - 2011
Y1 - 2011
N2 - 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.
AB - 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.
U2 - http://dx.doi.org/10.1093/hmg/ddr388
DO - http://dx.doi.org/10.1093/hmg/ddr388
M3 - Journal article
VL - 20
SP - 4732
EP - 4747
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 23
ER -
ID: 40154160