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

Cox, D. G. et al. (2011) Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers. Human Molecular Genetics, 20(23), pp. 4732-4747. (doi:10.1093/hmg/ddr388)

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Mutations in the <i>BRCA1</i> 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 <i>BRCA1</i> 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 <i>BRCA1</i> carried on the wild-type (non-mutated) copy of the <i>BRCA1</i> gene would modify the risk of breast cancer in carriers of <i>BRCA1</i> mutations. A total of 9874 <i>BRCA1</i> mutation carriers were available in the Consortium of Investigators of Modifiers of <i>BRCA1/2</i> (CIMBA) for haplotype analyses of <i>BRCA1</i>. Women carrying the rare allele of single nucleotide polymorphism rs16942 on the wild-type copy of <i>BRCA1</i> were at decreased risk of breast cancer (hazard ratio 0.86, 95% confidence interval 0.77–0.95, <i>P</i> = 0.003). Promoter <i>in vitro</i> assays of the major <i>BRCA1</i> 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 <i>BRCA1</i> modify risk of breast cancer among carriers of <i>BRCA1</i> mutations, possibly by altering the efficiency of <i>BRCA1</i> transcription.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Tobias, Professor Edward
Authors: Cox, D. G., Simard, J., Sinnett, D., Hamdi, Y., Soucy, P., Ouimet, M., Barjhoux, L., Verny-Pierre, C., McGuffog, L., Healey, S., Szabo, C., Greene, M. H., Mai, P. L., Andrulis, I. L., Thomassen, M., Gerdes, A.-M., Caligo, M. A., Friedman, E., Laitman, Y., Kaufman, B., Paluch, S. S., Borg, A., Karlsson, P., Stenmark Askmalm, M., Barbany Bustinza, G., Nathanson, K. L., Domchek, S. M., Rebbeck, T. R., Benitez, J., Hamann, U., Rookus, M. A., van den Ouweland, A. M. W., Ausems, M. G. E. M., Aalfs, C. M., van Asperen, C. J., Devilee, P., Gille, H. J. J. P., Peock, S., Frost, D., Evans, D. G., Eeles, R., Izatt, L., Adlard, J., Paterson, J., Eason, J., Godwin, A. K., Remon, M.-A., Moncoutier, V., Gauthier-Villars, M., Lasset, C., Giraud, S., Hardouin, A., Berthet, P., Sobol, H., Eisinger, F., Bressac de Paillerets, B., Caron, O., Delnatte, C., Goldgar, D., Miron, A., Ozcelik, H., Buys, S., Southey, M. C., Terry, M. B., Singer, C. F., Dressler, A.-C., Tea, M.-K., Hansen, T. V. O., Johannsson, O., Piedmonte, M., Rodriguez, G. C., Basil, J. B., Blank, S., Toland, A. E., Montagna, M., Isaacs, C., Blanco, I., Gayther, S. A., Moysich, K. B., Schmutzler, R. K., Wappenschmidt, B., Engel, C., Meindl, A., Ditsch, N., Arnold, N., Niederacher, D., Sutter, C., Gadzicki, D., Fiebig, B., Caldes, T., Laframboise, R., Nevanlinna, H., Chen, X., Beesley, J., Spurdle, A. B., Neuhausen, S. L., Ding, Y. C., Couch, F. J., Wang, X., Peterlongo, P., Manoukian, S., Bernard, L., Radice, P., Easton, D. F., Chenevix-Trench, G., Antoniou, A. C., Stoppa-Lyonnet, D., Mazoyer, S., Sinilnikova, O. M., and Tobias, E.S.
College/School:College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing > Clinical Specialities
Journal Name:Human Molecular Genetics

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