Summary
Reduced expression of BRCA1 has been implicated in sporadic breast cancer, although the mechanisms underlying this phenomenon remain unclear. To determine whether regulatory mutations could account for the reduced expression, we screened the promoter region by sequencing in 20 patients with sporadic disease. No mutations were detected; however, a new polymorphism consisting of a C-to-G base change within the β-promoter was identified, with the frequency of the G allele being 0.34. Close to complete linkage disequilibrium was found between this marker and the Pro871Leu polymorphism, situated in exon 11, which has previously been shown not to be associated with breast or ovarian cancer. This indicates that the C/G polymorphism is also unlikely to play a role in either disease. However, the strength of linkage disequilibrium between these markers permitted their use for rapid screening for genomic deletions within BRCA1. A series of 214 cases with familial breast cancer were analysed using this approach; 88/214 were heterozygous for the promoter polymorphism, thereby excluding a deletion in this region. Among the remaining patients, one hemizygous case reflecting a promoter deletion was successfully identified. Therefore, this study indicates that deletions within the β-promoter region of BRCA1 are an uncommon event in familial breast cancer. Furthermore, it suggests that mutations within the BRCA1 promoter are unlikely to account for the reported decreased expression of BRCA1 in sporadic disease.
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References
Ambrosone, C., Freudenheim, J., Marshall, J., Graham, S., Vena, J., Brasure, J., Michalek, A., Laughlin, R., Nemoto, T. & Shields, P. (1995). The association of polymorphic N-acetyltransferase (NAT 2) with breast cancer risk. Ann New York Acad Sci 768: 250–252.
Brown, M. A., Xu, C. F., Nicolai, H., Griffiths, B., Chambers, J. A., Black, D. & Solomon, E. (1996). The 5′ end of the BRCA1 gene lies within a duplicated region of human-chromosome 17q21. Oncogene 12: 2507–2513.
Catteau, A., Harris, W. H., Xu, C. F. & Solomon, E. (1999). Methylation of the BRCA1 promoter region in sporadic breast and ovarian cancer: correlation with disease characteristics. Oncogene,
Chakravarti, A., Buetow, K. H., Antonarakis, S. E., Waber, P. G., Boehm, C. D. & Kazazian, H. H. (1984). Nonuniform recombination within the human β-globin gene cluster. Am J Hum Genet 36: 1239–1258.
Couch, F. J., Weber, B. L., Borresen, A. L., Brody, L., Casey, G., Devilee, P., Fitzgerald, M., Friend, S., Gayther, S., Goldgar, D., Murphy, P., Szabo, C., Weber, B., Wiseman, R., Anderson, T., Durocher, F., Ganguly, A., King, M. C., Lenoir, G., Narod, S., Olopade, O., Plummer, S., Ponder, B., Serova, O., Simard, J., Stratton, M. & Warren, B. (1996). Mutations and polymorphisms in the familial early-onset breast-cancer (BRCA1) gene. Hum Mutat 8: 8–18.
Dobrovic, A. & Simpfendorfer, D. (1997). Methylation of the BRCA1 gene in sporadic breast cancer. Cancer Res 57: 3347–3350.
Dunning, A. M., Chiano, M., Smith, N. R., Dearden, J., Gore, M., Oakes, S., Wilson, C., Stratton, M., Peto, J., Easton, D., Clayton, D. & Ponder, B. A. J. (1997). Common BRCA1 variants and susceptibility to breast and ovarian-cancer in the general population. Hum Mol Genet 6: 285–289.
Feigelson, H. S., Coetzee, G. A., Kolonel, L. N., Ross, R. K. & Henderson, B. E. (1997). A polymorphism in the CYP17 Gene increases the risk of breast cancer. Cancer Res 57: 1063–1065.
Ford, D., Easton, D. F. & Peto, J. (1995). Estimates of the gene-frequency of BRCA1 and its contribution to breast and ovarian-cancer incidence. Am J Hum Genet 57: 1457–1462.
Futreal, P. A., Liu, Q., Shattuck-Eidens, D., Cochran, C., Harshman, K., Tavigian, S., Bennett, L. M., Haugen-Strano, A., Swensen, J., Miki, Y., Eddington, K., McClure, M., Frye, C., Weaver-Feldhaus, J., Ding, W., Gholami, Z., Soderkvist, P., Terry, L., Jhanwar, S., Berchuck, A., Iglehart, J. D., Marks, J., Ballinger, D. G., Barrett, J. C., Skolnick, M. H., Kamb, A. & Wiseman, R. (1994). BRCA1 mutations in primary breast and ovarian carcinomas. Science 266: 120–122.
Hosking, L., Trowsdale, J., Nicolai, H., Solomon, E., Foulkes, W., Stamp, G., Signer, E. & Jeffreys, A. (1995). A somatic BRCA1 mutation in an ovarian tumor. Nature Genet 9: 343–344.
Krontiris, T. G., Devlin, D. B., Karp, D. D., Robert, N. J. & Risch, N. (1993). An association between the risk of cancer and mutations in HRAS1 minisatellite locus. New Engl J Med 329: 517–523.
Mancini, D. N., Rodenhiser, D. I., Ainsworth, P. J., O’Malley, F. P., Singh, S. M., Xing, W. & Archer, T. K. (1998). CpG methylation within the 5′ regulatory region of the BRCA1 gene is tumor specific and includes a putative CREB binding site. Oncogene 16: 1161–1169.
Merajver, S. D., Pham, T. M., Caduff, R. F., Chen, M., Poy, E. L., Cooney, K. A., Weber, B. L., Collins, F. S., Johnston, C. & Frank, T. S. (1995). Somatic mutations in the Brca1 gene in sporadic ovarian-tumors. Nature Genet 9: 439–443.
Miki, Y., Swensen, J., Shattuck-Eidens, D., Futreal, P. A., Harshman, K., Tavtigian, S., Liu, Q., Cochran, C., Bennet, L. M., Ding, W., Bell, R., Rosenthal, J., Hussey, C., Tran, T., McClure, M., Frye, C., Hattier, T., Phelps, R., Haugen-Strano, A., Katcher, H., Yakumo, K., Gholami, Z., Shaffer, D., Sone, S., Bayer, S., Wray, C., Bogden, R., Dayananth, P., Ward, J., Tonin, P., Narod, S., Bristow, P. K., Norris, F. H., Helvering, L., Morrison, P., Rosteck, P., Lai, M., Barrett, J. C., Lewis, C., Neuhausen, S., Cannon-Albright, L., Goldgar, D., Wiseman, R., Kamb, A. & Skolnick, M. H. (1994). A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266: 66–71.
Newton, C. R., Graham, A., Heptinstall, L. E., Powell, S. J., Summers, C., Kalsheker, N., Smith, J. C. & Markham, A. F. (1989). Analysis of any point mutation in DNA. The amplification refractory mutation system (ARMS). Nucleic Acios Res 17: 1503–1516.
Petrij-Bosch, A., Peelen, T., Van Vliet, M., Van Eijk, R., Olmer, R., Drusedau, M., Hogervorst, F. B. L., Hageman, S., Arts, P. J. W., Ligtenberg, M. J. L., Meijers-Heijboer, H., Klijn, J. G. M., Vasen, H. F. A., Cornelisse, C. J., Van’t Veer, L. J., Bakker, E., Van Ommen, G-JB & Devilee, P. (1997). BRCA1 genomic deletions are major founder mutations in Dutch breast cancer patients. Nature Genet 17: 341–345.
Puget, N., Torchard, D., Serovasinilnikova, O. M., Lynch, H. T., Feunteun, J., Lenoir, G. M. & Mazoyer, S. (1997). A 1-kb alu-mediated germ-line deletion removing BRCA1 exon-17. Cancer Res 57: 828–831.
Smith, T. M., Lee, M. K., Szabo, C. I., Jerome, N., McEuen, M., Taylor, M., Hood, L. & King, M. C. (1996). Complete genomic sequence and analysis of 117 kb of human DNA containing the gene BRCA1. Genome Res 6: 1029–1049.
Swensen, J., Hohhman, M., Skolnick, M. H. & Neuhausen, S. L. (1997). Identification of a 14 kb deletion involving the promoter region of BRCA1 in a breast cancer family. Hum Mol Genet 6: 1513–1517.
Thompson, M. E., Jensen, R. A., Obermiller, P. S., Page, D. L. & Holt, J. T. (1995). Decreased expression of BRCA1 accelerates growth and is often present during sporadic breast-cancer progression. Nature Genet 9: 444–450.
Xu, C-F, Brown, M. A., Chambers, J. A., Griffiths, B., Nicolai, H. & Solomon, E. (1995). Distinct transcription start sites generate two forms of BRCA1 mRNA. Hum Mol Genet 4: 2259–2264.
Xu, C-F & Solomon, E. (1996). Mutations of the BRCA1 gene in human cancer. Semin Cancer Biol 7: 33–40.
Xu, C-F, Chambers, J. A. & Solomon, E. (1997). Complex regulation of the BRCA1 gene. J Biol Chem 272: 20994–20997.
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Catteau, A., Xu, CF., Brown, M. et al. Identification of a C/G polymorphism in the promoter region of the BRCA1 gene and its use as a marker for rapid detection of promoter deletions. Br J Cancer 79, 759–763 (1999). https://doi.org/10.1038/sj.bjc.6690122
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DOI: https://doi.org/10.1038/sj.bjc.6690122