Abstract
Breast cancer results from genetic and environmental factors leading to the accumulation of mutations in essential genes. Genetic predisposition may have a strong, almost singular effect, as with BRCA1 and BRCA2, or may represent the cumulative effects of multiple low-penetrance susceptibility alleles. Here we review high- and low-penetrance breast-cancer-susceptibility alleles and discuss ongoing efforts to identify additional susceptibility genes. Ultimately these discoveries will lead to individualized breast cancer risk assessment and a reduction in breast cancer incidence.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Couch, F.J. et al. BRCA1 mutations in women attending clinics that evaluate the risk of breast cancer. N. Engl. J. Med. 336, 1409–1415 (1997).
Peto, J. et al. Prevalence of BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer [see comments]. J. Natl. Cancer Inst. 91, 943–949 (1999).
Easton, D.F., Bishop, D.T., Ford, D. & Crockford, G.P. Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. The Breast Cancer Linkage Consortium. Am. J.Hum. Genet. 52, 678–701 (1993).
Struewing, J.P., Tarone, R.E., Brody, L.C., Li, F.P. & Boice, J.D. Jr. BRCA1 mutations in young women with breast cancer. Lancet 347, 1493 (1996).
Fodor, F.H. et al. Frequency and carrier risk associated with common BRCA1 and BRCA2 mutations in Ashkenazi Jewish breast cancer patients. Am. J. Hum. Genet. 63, 45–51 (1998).
Easton, D.F., Narod, S.A., Ford, D. & Steel, M. The genetic epidemiology of BRCA1. Breast Cancer Linkage Consortium. Lancet 344, 761 (1994).
Easton, D.F., Ford, D. & Bishop, D.T. Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Am. J. Hum. Genet. 56, 265–271 (1995).
Struewing, J.P. et al. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N. Engl. J. Med. 336, 1401–1408 (1997).
Ford, D., Easton, D.F., Bishop, D.T., Narod, S.A. & Goldgar, D.E. Risks of cancer in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Lancet 343, 692–695 (1994).
Shih, H. et al. BRCA1 and BRCA2 mutations in breast cancer families with multiple primary cancers. Clin Cancer Res 6, 4259–4264 (2000).
Miki, Y. et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266, 66–71 (1994).
Chapman, M.S. & Verma, I.M. Transcriptional activation by BRCA1. Nature 382, 678–679 (1996).
Zhang, H. et al. BRCA1 physically associates with p53 and stimulates its transcriptional activity. Oncogene 16, 1713–1721 (1998).
Scully, R. et al. Association of BRCA1 with Rad51 in mitotic and meiotic cells. Cell 88, 265–275 (1997).
Scully, R. & Livingston, D.M. In search of the tumour-suppressor functions of BRCA1 and BRCA2. Nature 408, 429–432 (2000).
Cortez, D., Wang, Y., Qin, J. & Elledge, S.J. Requirement of ATM-dependent phosphorylation of brca1 in the DNA damage response to double-strand breaks. Science 286, 1162–1166 (1999).
Lee, J.S., Collins, K.M., Brown, A.L., Lee, C.H. & Chung, J.H. hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response. Nature 404, 201–204 (2000).
Larson, J.S., Tonkinson, J.L. & Lai, M.T. A BRCA1 mutant alters G2-M cell cycle control in human mammary epithelial cells. Cancer Res. 57, 3351–3355 (1997).
Gowen, L.C., Avrutskaya, A.V., Latour, A.M., Koller, B.H. & Leadon, S.A. BRCA1 required for transcription-coupled repair of oxidative DNA damage. Science 281, 1009–1012 (1998).
Zhong, Q. et al. Association of BRCA1 with the hRad50-hMre11-p95 complex and the DNA damage response. Science 285, 747–750 (1999).
Easton, D.F. & Consortium, T.B.C.L. Cancer risks in BRCA2 mutation carriers. J. Natl. Cancer Inst. 91, 1310–1316 (1999).
Warner, E. et al. Prevalence and penetrance of BRCA1 and BRCA2 gene mutations in unselected Ashkenazi Jewish women with breast cancer. J Natl Cancer Inst 91, 1241–1247 (1999).
Wooster R et al. Identification of the breast cancer susceptibility gene BRCA2. Nature 378, 789–92 (1995).
Tavtigian, S.V. et al. The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds. Nature Genet. 12, 333–337 (1996).
Chen, J.J., Silver, D., Cantor, S., Livingston, D.M. & Scully, R. BRCA1, BRCA2, and Rad51 operate in a common DNA damage response pathway. Cancer Res. 59, 1752s–1756s (1999).
Connor, F. et al. Tumorigenesis and a DNA repair defect in mice with a truncating Brca2 mutation. Nature Genet. 17, 423–430 (1997).
Friedman, L.S. et al. Thymic lymphomas in mice with a truncating mutation in Brca2. Cancer Res. 58, 1338–1343 (1998).
Patel, K.J. et al. Involvement of Brca2 in DNA repair. Mol. Cell 1, 347–357 (1998).
Sharan, S.K. et al. Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2. Nature 386, 804–810 (1997).
Nasmyth K. Peters JM . Uhlmann F. Splitting the chromosome: cutting the ties that bind sister chromatids. Science. 288,1379–1385 (2000).
Boardman, L.A. et al. Increased risk for cancer in patients with the Peutz-Jeghers syndrome. Ann. Int. Med. 128, 896–899 (1998).
Liaw, D. et al. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nature Genet. 16, 64–67 (1997).
Wooster, R. et al. A germline mutation in the androgen receptor gene in two brothers with breast cancer and Reifenstein syndrome. Nature Genet. 2, 132–134 (1992).
Lobaccaro, J.M. et al. Androgen receptor gene mutation in male breast cancer. Hum. Mol. Genet. 2, 1799–1802 (1993).
Malkin, D. et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250, 1233–1238 (1990).
Morrell, D., Cromartie, E. & Swift, M. Mortality and cancer incidence in 263 patients with ataxia-telangiectasia. J. Natl. Cancer Inst. 77, 89–92 (1986).
Swift, M., Reitnauer, P.J., Morrell, D. & Chase, C.L. Breast and other cancers in families with ataxia-telangiectasia. N. Engl. J. Med. 316, 1289–1294 (1987).
Swift, M., Morrell, D., Massey, R.B. & Chase, C.L. Incidence of cancer in 161 families affected by ataxia-telangiectasia. N. Engl. J. Med. 325, 1831–1836 (1991).
Inskip, H.M., Kinlen, L.J., Taylor, A.M., Woods, C.G. & Arlett, C.F. Risk of breast cancer and other cancers in heterozygotes for ataxia-telangiectasia. Br. J. Cancer 79, 1304–1307 (1999).
Janin, N. et al. Breast cancer risk in ataxia telangiectasia (AT) heterozygotes: haplotype study in French AT families. Br. J. Cancer 80, 1042–1045 (1999).
Broeks, A. et al. ATM-heterozygous germline mutations contribute to breast cancer-susceptibility. Am. J. Hum. Genet. 66, 494–500 (2000).
FitzGerald, M.G. et al. Heterozygous ATM mutations do not contribute to early onset of breast cancer. Nature Genet. 15, 307–310 (1997).
Izatt, L. et al. Identification of germline missense mutations and rare allelic variants in the ATM gene in early-onset breast cancer. Genes Chrom. Cancer 26, 286–294 (1999).
Chen, J., Birkholtz, G.G., Lindblom, P., Rubio, C. & Lindblom, A. The role of ataxia-telangiectasia heterozygotes in familial breast cancer. Cancer Res. 58, 1376–1379 (1998).
Vorechovsky, I. et al. ATM mutations in cancer families. Cancer Res. 56, 4130–4133 (1996).
Laake, K. et al. Screening breast cancer patients for Norwegian ATM mutations. Br. J. Cancer 83, 1650–1653 (2000).
Kainu, T. et al. Somatic deletions in hereditary breast cancers implicate 13q21 as a putative novel breast cancer susceptibility locus. Proc. Natl. Acad. Sci. USA 97, 9603–9608 (2000).
Thompson, D. et al. Chromsome 13q: Two genes too many? Proc. Am. Assoc. Cancer Res. (2001).
Ford, D. et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am. J.Hum. Genet. 62, 676–689 (1998).
Lakhani, S.R. et al. The pathology of familial breast cancer: histological features of cancers in families not attributable to mutations in BRCA1 or BRCA2. Clin. Cancer Res. 6, 782–789 (2000).
Hedenfalk, I. et al. Gene-expression profiles in hereditary breast cancer. N. Engl. J. Med. 344, 539 (2001).
Anonymous. Prevalence and penetrance of BRCA1 and BRCA2 mutations in a population-based series of breast cancer cases. Anglian Breast Cancer Study Group. Br. J. Cancer 83, 1301–1308 (2000).
Claus, E.B., Schildkraut, J., Iversen, E.S., Berry, D. & Parmigiani, G. Effect of BRCA1 and BRCA2 on the association between breast cancer risk and family history. J. Natl. Cancer. Inst. 90, 1824–1890 (1998).
Krontiris, T.G., Devlin, B., Karp, D.D., Robert, N. J. & Risch, N. An association between the risk of cancer and mutations in the HRAS1 minisatellite locus. N. Engl. J. Med. 329, 517–523 (1993).
Phelan, C.M. et al. Ovarian cancer risk in BRCA1 carriers is modified by the HRAS1 variable number of tandem repeat (VNTR) locus. Nature Genet. 12, 309–311 (1996).
Rebbeck, T. et al. Modification of BRCA1-associated breast cancer risk by the polymorphic androgen receptor CAG repeat. Am. J. Hum. Genet. 64, 1371–1377 (1999).
Park, J.J. et al. Breast cancer susceptibility gene 1 (BRCAI) is a coactivator of the androgen receptor. Cancer Res. 60, 5946–5949 (2000).
Tirkkonen, M. et al. Distinct somatic genetic changes associated with tumor progression in carriers of BRCA1 and BRCA2 germ-line mutations. Cancer Res. 57, 1222–1227 (1997).
Kruglyak, L. Prospects for whole-genome linkage disequilibrium mapping of common disease genes. Nature Genet. 22, 139–144 (1999).
Eisen, A., Rebbeck, T.R., Wood, W.C. & Weber, B.L. Prophylactic surgery in women with a hereditary predisposition to breast and ovarian cancer. J. Clin. Oncol. 18, 1980–1995 (2000).
Peto, J. & Mack, T.M. High constant incidence in twins and other relatives of women with breast cancer. Nature Genet. 26, 411–414 (2000).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Nathanson, K., Wooster, R. & Weber, B. Breast cancer genetics: What we know and what we need. Nat Med 7, 552–556 (2001). https://doi.org/10.1038/87876
Issue Date:
DOI: https://doi.org/10.1038/87876
This article is cited by
-
Significant association of BRCA1 (rs1799950), BRCA2 (rs144848) and TP53 (rs1042522) polymorphism with breast cancer risk in Pashtun population of Khyber Pakhtunkhwa, Pakistan
Molecular Biology Reports (2023)
-
A “turn-on” DNA-scaffolded silver-nanocluster probe for detection of tumor-related mRNA
Analytical Sciences (2022)
-
The prognostic significance of Flap Endonuclease 1 (FEN1) in breast ductal carcinoma in situ
Breast Cancer Research and Treatment (2021)
-
Design and Synthesis of BRCA1 (856-871) Analogous and their Interactions with RAD51 (158-180)
International Journal of Peptide Research and Therapeutics (2021)
-
Design of BRC analogous peptides based on the complex BRC8–RAD51 and the preliminary study on the peptide structures
Amino Acids (2020)