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 5 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.
| Original language | English |
|---|---|
| Pages (from-to) | 4732-4747 |
| Number of pages | 16 |
| Journal | Human Molecular Genetics |
| Volume | 20 |
| Issue number | 23 |
| DOIs | |
| State | Published - Dec 1 2011 |
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In: Human Molecular Genetics, Vol. 20, No. 23, 01.12.2011, p. 4732-4747.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
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 - Glendon, Gord
AU - Selander, Teresa
AU - Weerasooriya, Nayana
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
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, Loeter Devilee
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 - Giraud, Sophie
AU - Hardouin, Agnès
AU - Berthet, Pascaline
AU - Sobol, Hagay
AU - Eisinger, François
AU - de Paillerets, Brigitte Bressac
AU - Caron, Olivier
AU - Delnatte, Capucine
AU - Goldgar, David
AU - Miron, Alex
AU - Ozcelik, Hilmi
AU - Buys, Saundra
AU - Southey, Melissa C.
AU - Terry, Mary Beth
AU - Singer, Christian F.
AU - Dressler, Anne Catharina
AU - Tea, Muy Kheng
AU - Hansen, Thomas V.O.
AU - Johannsson, Oskar
AU - Piedmonte, Marion
AU - Rodriguez, Gustavo C.
AU - Basil, Jack B.
AU - Blank, Stephanie
AU - Toland, Amanda E.
AU - Montagna, Marco
AU - Isaacs, Claudine
AU - Blanco, Ignacio
AU - Gayther, Simon A.
AU - Moysich, Kirsten B.
AU - Schmutzler, Rita K.
AU - Wappenschmidt, Barbara
AU - Engel, Christoph
AU - Meindl, Alfons
AU - Ditsch, Nina
AU - Arnold, Norbert
AU - Niederacher, Dieter
AU - Sutter, Christian
AU - Gadzicki, Dorothea
AU - Fiebig, Britta
AU - Caldes, Trinidad
AU - Laframboise, Rachel
AU - Nevanlinna, Heli
AU - Chen, Xiaoqing
AU - Beesley, Jonathan
AU - Spurdle, Amanda B.
AU - Neuhausen, Susan L.
AU - Ding, Yuan C.
AU - Couch, Fergus J.
AU - Wang, Xianshu
AU - Peterlongo, Paolo
AU - Manoukian, Siranoush
AU - Bernard, Loris
AU - Radice, Paolo
AU - Easton, Douglas F.
AU - Chenevix-Trench, Georgia
AU - Antoniou, Antonis C.
AU - Stoppa-Lyonnet, Dominique
AU - Mazoyer, Sylvie
AU - Sinilnikova, Olga M.
AU - Nordling, Margareta
AU - Bergman, Annika
AU - Einbeigi, Zakaria
AU - Stenmark-Askmalm, Marie
AU - Liedgren, Sigrun
AU - Borg, Åke
AU - Loman, Niklas
AU - Olsson, Håkan
AU - Kristoffersson, Ulf
AU - Soller, Maria
AU - Jernström, Helena
AU - Harbst, Katja
AU - Henriksson, Karin
AU - Lindblom, Annika
AU - Arver, Brita
AU - von Wachenfeldt, Anna
AU - Liljegren, Annelie
AU - Barbany-Bustinza, Gisela
AU - Rantala, Johanna
AU - Melin, Beatrice
AU - Grönberg, Henrik
AU - Stattin, Eva Lena
AU - Emanuelsson, Monica
AU - Ehrencrona, Hans
AU - Brandell, Richard Rosenquist
AU - Dahl, Niklas
AU - Hogervorst, F. B.L.
AU - Verhoef, S.
AU - Verheus, M.
AU - van't Veer, L. J.
AU - van Leeuwen, F. E.
AU - Rookus, M. A.
AU - Collée, M.
AU - Jager, A.
AU - Hooning, M. J.
AU - Tilanus-Linthorst, M. M.A.
AU - Seynaeve, C.
AU - van Asperen, C. J.
AU - Wijnen, J. T.
AU - Vreeswijk, M. P.
AU - Tollenaar, R. A.
AU - Ligtenberg, M. J.
AU - Hoogerbrugge, N.
AU - Ausems, M. G.
AU - van der Luijt, R. B.
AU - Aalfs, C. M.
AU - van Os, T. A.
AU - Gille, J. J.P.
AU - Waisfisz, Q.
AU - Meijers-Heijboer, H. E.J.
AU - Gomez-Garcia, E. B.
AU - van Roozendaal, C. E.
AU - Blok, Marinus J.
AU - Caanen, B.
AU - Oosterwijk, J. C.
AU - van der Hout, A. H.
AU - Mourits, M. J.
AU - Vasen, H. F.
AU - Peock, Susan
AU - Cook, Margaret
AU - Frost, Debra
AU - Platte, Radka
AU - Miedzybrodzka, Zosia
AU - Gregory, Helen
AU - Morrison, Patrick
AU - Jeffers, Lisa
AU - Cole, Trevor
AU - Ong, Kai Ren
AU - Hoffman, Jonathan
AU - Donaldson, Alan
AU - James, Margaret
AU - Paterson, Joan
AU - Downing, Sarah
AU - Taylor, Amy
AU - Murray, Alexandra
AU - Rogers, Mark T.
AU - McCann, Emma
AU - Kennedy, M. John
AU - Barton, David
AU - Porteous, Mary
AU - Drummond, Sarah
AU - Brewer, Carole
AU - Kivuva, Emma
AU - Searle, Anne
AU - Goodman, Selina
AU - Hill, Kathryn
AU - Davidson, Rosemarie
AU - Murday, Victoria
AU - Bradshaw, Nicola
AU - Snadden, Lesley
AU - Longmuir, Mark
AU - Watt, Catherine
AU - Gibson, Sarah
AU - Haque, Eshika
AU - Tobias, Ed
AU - Duncan, Alexis
AU - Izatt, Louise
AU - Jacobs, Chris
AU - Langman, Caroline
AU - Whaite, Anna
AU - Dorkins, Huw
AU - Barwell, Julian
AU - Adlard, Julian
AU - Chu, Carol
AU - Miller, Julie
AU - Ellis, Ian
AU - Houghton, Catherine
AU - Lalloo, Fiona
AU - Taylor, Jane
AU - Side, Lucy
AU - Male, Alison
AU - Berlin, Cheryl
AU - Eason, Jacqueline
AU - Collier, Rebecca
AU - Douglas, Fiona
AU - Claber, Oonagh
AU - Jobson, Irene
AU - Walker, Lisa
AU - McLeod, Diane
AU - Halliday, Dorothy
AU - Durell, Sarah
AU - Stayner, Barbara
AU - Eeles, Ros
AU - Shanley, Susan
AU - Rahman, Nazneen
AU - Houlston, Richard
AU - Bancroft, Elizabeth
AU - D'Mello, Lucia
AU - Page, Elizabeth
AU - Ardern-Jones, Audrey
AU - Kohut, Kelly
AU - Wiggins, Jennifer
AU - Castro, Elena
AU - Mitra, Anita
AU - Robertson, Lisa
AU - Cook, Jackie
AU - Quarrell, Oliver
AU - Bardsley, Cathryn
AU - Hodgson, Shirley
AU - Goff, Sheila
AU - Brice, Glen
AU - Winchester, Lizzie
AU - Eddy, Charlotte
AU - Tripathi, Vishakha
AU - Attard, Virginia
AU - Eccles, Diana
AU - Lucassen, Anneke
AU - Crawford, Gillian
AU - McBride, Donna
AU - Smalley, Sarah
AU - Sinilnikova, Olga
AU - Barjhoux, Laure
AU - Verny-Pierre, Carole
AU - Giraud, Sophie
AU - Léone, Mélanie
AU - Mazoyer, Sylvie
AU - Stoppa-Lyonnet, Dominique
AU - Gauthier-Villars, Marion
AU - Buecher, Bruno
AU - Houdayer, Claude
AU - Moncoutier, Virginie
AU - Belotti, Muriel
AU - Tirapo, Carole
AU - de Pauw, Antoine
AU - Bressac-de-Paillerets, Brigitte
AU - Remenieras, Audrey
AU - Byrde, Véronique
AU - Caron, Olivier
AU - Lenoir, Gilbert
AU - Bignon, Yves Jean
AU - Uhrhammer, Nancy
AU - Bonadona, Valérie
AU - Hardouin, Agnès
AU - Berthet, Pascaline
AU - Sobol, Hagay
AU - Bourdon, Violaine
AU - Noguchi, Tetsuro
AU - Eisinger, François
AU - Coulet, Florence
AU - Colas, Chrystelle
AU - Soubrier, Florent
AU - Coupier, Isabelle
AU - Pujol, Pascal
AU - Peyrat, Jean Philippe
AU - Fournier, Joëlle
AU - Révillion, Françoise
AU - Vennin, Philippe
AU - Adenis, Claude
AU - Rouleau, Etienne
AU - Lidereau, Rosette
AU - Demange, Liliane
AU - Nogues, Catherine
AU - Muller, Danièle
AU - Fricker, Jean Pierre
AU - Longy, Michel
AU - Sevenet, Nicolas
AU - Toulas, Christine
AU - Guimbaud, Rosine
AU - Gladieff, Laurence
AU - Feillel, Viviane
AU - Leroux, Dominique
AU - Dreyfus, Hélène
AU - Rebischung, Christine
AU - Coron, Fanny
AU - Faivre, Laurence
AU - Prieur, Fabienne
AU - Lebrun, Marine
AU - Ferrer, Sandra Fert
AU - Frénay, Marc
AU - Vénat-Bouvet, Laurence
PY - 2011/12/1
Y1 - 2011/12/1
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 5 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 5 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.
UR - https://www.scopus.com/pages/publications/81255190718
U2 - 10.1093/hmg/ddr388
DO - 10.1093/hmg/ddr388
M3 - Article
C2 - 21890493
AN - SCOPUS:81255190718
SN - 0964-6906
VL - 20
SP - 4732
EP - 4747
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 23
ER -