Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 2001 Jul;85(1):36–40. doi: 10.1054/bjoc.2001.1777

CAG and GGC repeat polymorphisms in the androgen receptor gene and breast cancer susceptibility in BRCA1/2 carriers and non-carriers

L Kadouri 1,2, D F Easton 3, S Edwards 2, A Hubert 1, Z Kote-Jarai 2, B Glaser 4, F Durocher 3, D Abeliovich 5, T Peretz 1, R A Eeles 2,6
PMCID: PMC2363908  PMID: 11437399

Abstract

Variation in the penetrance estimates for BRCA1 and BRCA2 mutations carriers suggests that other genetic polymorphisms may modify the cancer risk in carriers. A previous study has suggested that BRCA1 carriers with longer lengths of the CAG repeat in the androgen receptor (AR) gene are at increased risk of breast cancer (BC). We genotyped 188 BRCA1/2 carriers (122 affected and 66 unaffected with breast cancer), 158 of them of Ashkenazi origin, 166 BC cases without BRCA1/2 mutations and 156 Ashkenazi control individuals aged over 56 for the AR CAG and GGC repeats. In carriers, risk analyses were conducted using a variant of the log-rank test, assuming two sets of risk estimates in carriers: penetrance estimates based on the Breast Cancer Linkage Consortium (BCLC) studies of multiple case families, and lower estimates as suggested by population-based studies. We found no association of the CAG and GGC repeats with BC risk in either BRCA1/2 carriers or in the general population. Assuming BRCA1/2 penetrance estimates appropriate to the Ashkenazi population, the estimated RR per repeat adjusted for ethnic group (Ashkenazi and non-Ashkenazi) was 1.05 (95%CI 0.97–1.17) for BC and 1.00 (95%CI 0.83–1.20) for ovarian cancer (OC) for CAG repeats and 0.96 (95%CI 0.80–1.15) and 0.90 (95%CI 0.60–1.22) respectively for GGC repeats. The corresponding RR estimates for the unselected case–control series were 1.00 (95%CI 0.91–1.10) for the CAG and 1.05 (95%CI 0.90–1.22) for the GGC repeats. The estimated relative risk of BC in carriers associated with ≥28 CAG repeats was 1.08 (95%CI 0.45–2.61). Furthermore, no significant association was found if attention was restricted to the Ashkenazi carriers, or only to BRCA1 or BRCA2 carriers. We conclude that, in contrast to previous observations, if there is any effect of the AR repeat length on BRCA1 penetrance, it is likely to be weak. © 2001 Cancer Research Campaign http://www.bjcancer.com

Keywords: BRCA1/2, androgen receptor, polymorphisms, breast cancer risk

Full Text

The Full Text of this article is available as a PDF (211.1 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adams J. B. Adrenal androgens and human breast cancer: a new appraisal. Breast Cancer Res Treat. 1998 Sep;51(2):183–188. doi: 10.1023/a:1006050720900. [DOI] [PubMed] [Google Scholar]
  2. Bulbrook R. D., Hayward J. L., Spicer C. C. Relation between urinary androgen and corticoid excretion and subsequent breast cancer. Lancet. 1971 Aug 21;2(7721):395–398. doi: 10.1016/s0140-6736(71)90113-9. [DOI] [PubMed] [Google Scholar]
  3. Cauley J. A., Lucas F. L., Kuller L. H., Stone K., Browner W., Cummings S. R. Elevated serum estradiol and testosterone concentrations are associated with a high risk for breast cancer. Study of Osteoporotic Fractures Research Group. Ann Intern Med. 1999 Feb 16;130(4 Pt 1):270–277. doi: 10.7326/0003-4819-130-4_part_1-199902160-00004. [DOI] [PubMed] [Google Scholar]
  4. Dunning A. M., McBride S., Gregory J., Durocher F., Foster N. A., Healey C. S., Smith N., Pharoah P. D., Luben R. N., Easton D. F. No association between androgen or vitamin D receptor gene polymorphisms and risk of breast cancer. Carcinogenesis. 1999 Nov;20(11):2131–2135. doi: 10.1093/carcin/20.11.2131. [DOI] [PubMed] [Google Scholar]
  5. 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. 1995 Jan;56(1):265–271. [PMC free article] [PubMed] [Google Scholar]
  6. Edwards A., Hammond H. A., Jin L., Caskey C. T., Chakraborty R. Genetic variation at five trimeric and tetrameric tandem repeat loci in four human population groups. Genomics. 1992 Feb;12(2):241–253. doi: 10.1016/0888-7543(92)90371-x. [DOI] [PubMed] [Google Scholar]
  7. Edwards S. M., Badzioch M. D., Minter R., Hamoudi R., Collins N., Ardern-Jones A., Dowe A., Osborne S., Kelly J., Shearer R. Androgen receptor polymorphisms: association with prostate cancer risk, relapse and overall survival. Int J Cancer. 1999 Oct 22;84(5):458–465. doi: 10.1002/(sici)1097-0215(19991022)84:5<458::aid-ijc2>3.0.co;2-y. [DOI] [PubMed] [Google Scholar]
  8. Ford D., Easton D. F., Stratton M., Narod S., Goldgar D., Devilee P., Bishop D. T., Weber B., Lenoir G., Chang-Claude J. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet. 1998 Mar;62(3):676–689. doi: 10.1086/301749. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Hakimi J. M., Schoenberg M. P., Rondinelli R. H., Piantadosi S., Barrack E. R. Androgen receptor variants with short glutamine or glycine repeats may identify unique subpopulations of men with prostate cancer. Clin Cancer Res. 1997 Sep;3(9):1599–1608. [PubMed] [Google Scholar]
  10. Ingles S. A., Ross R. K., Yu M. C., Irvine R. A., La Pera G., Haile R. W., Coetzee G. A. Association of prostate cancer risk with genetic polymorphisms in vitamin D receptor and androgen receptor. J Natl Cancer Inst. 1997 Jan 15;89(2):166–170. doi: 10.1093/jnci/89.2.166. [DOI] [PubMed] [Google Scholar]
  11. Isola J. J. Immunohistochemical demonstration of androgen receptor in breast cancer and its relationship to other prognostic factors. J Pathol. 1993 May;170(1):31–35. doi: 10.1002/path.1711700106. [DOI] [PubMed] [Google Scholar]
  12. Kazemi-Esfarjani P., Trifiro M. A., Pinsky L. Evidence for a repressive function of the long polyglutamine tract in the human androgen receptor: possible pathogenetic relevance for the (CAG)n-expanded neuronopathies. Hum Mol Genet. 1995 Apr;4(4):523–527. doi: 10.1093/hmg/4.4.523. [DOI] [PubMed] [Google Scholar]
  13. Kuenen-Boumeester V., Van der Kwast T. H., Claassen C. C., Look M. P., Liem G. S., Klijn J. G., Henzen-Logmans S. C. The clinical significance of androgen receptors in breast cancer and their relation to histological and cell biological parameters. Eur J Cancer. 1996 Aug;32A(9):1560–1565. doi: 10.1016/0959-8049(96)00112-8. [DOI] [PubMed] [Google Scholar]
  14. La Spada A. R., Wilson E. M., Lubahn D. B., Harding A. E., Fischbeck K. H. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature. 1991 Jul 4;352(6330):77–79. doi: 10.1038/352077a0. [DOI] [PubMed] [Google Scholar]
  15. Peto J., Collins N., Barfoot R., Seal S., Warren W., Rahman N., Easton D. F., Evans C., Deacon J., Stratton M. R. Prevalence of BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer. J Natl Cancer Inst. 1999 Jun 2;91(11):943–949. doi: 10.1093/jnci/91.11.943. [DOI] [PubMed] [Google Scholar]
  16. Rebbeck T. R., Kantoff P. W., Krithivas K., Neuhausen S., Blackwood M. A., Godwin A. K., Daly M. B., Narod S. A., Garber J. E., Lynch H. T. Modification of BRCA1-associated breast cancer risk by the polymorphic androgen-receptor CAG repeat. Am J Hum Genet. 1999 May;64(5):1371–1377. doi: 10.1086/302366. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Secreto G., Toniolo P., Berrino F., Recchione C., Cavalleri A., Pisani P., Totis A., Fariselli G., Di Pietro S. Serum and urinary androgens and risk of breast cancer in postmenopausal women. Cancer Res. 1991 May 15;51(10):2572–2576. [PubMed] [Google Scholar]
  18. Secreto G., Toniolo P., Pisani P., Recchione C., Cavalleri A., Fariselli G., Totis A., Di Pietro S., Berrino F. Androgens and breast cancer in premenopausal women. Cancer Res. 1989 Jan 15;49(2):471–476. [PubMed] [Google Scholar]
  19. Sleddens H. F., Oostra B. A., Brinkmann A. O., Trapman J. Trinucleotide (GGN) repeat polymorphism in the human androgen receptor (AR) gene. Hum Mol Genet. 1993 Apr;2(4):493–493. doi: 10.1093/hmg/2.4.493. [DOI] [PubMed] [Google Scholar]
  20. Sleddens H. F., Oostra B. A., Brinkmann A. O., Trapman J. Trinucleotide repeat polymorphism in the androgen receptor gene (AR). Nucleic Acids Res. 1992 Mar 25;20(6):1427–1427. doi: 10.1093/nar/20.6.1427-a. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Spurdle A. B., Dite G. S., Chen X., Mayne C. J., Southey M. C., Batten L. E., Chy H., Trute L., McCredie M. R., Giles G. G. Androgen receptor exon 1 CAG repeat length and breast cancer in women before age forty years. J Natl Cancer Inst. 1999 Jun 2;91(11):961–966. doi: 10.1093/jnci/91.11.961. [DOI] [PubMed] [Google Scholar]
  22. Struewing J. P., Hartge P., Wacholder S., Baker S. M., Berlin M., McAdams M., Timmerman M. M., Brody L. C., Tucker M. A. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med. 1997 May 15;336(20):1401–1408. doi: 10.1056/NEJM199705153362001. [DOI] [PubMed] [Google Scholar]
  23. Thorlacius S., Struewing J. P., Hartge P., Olafsdottir G. H., Sigvaldason H., Tryggvadottir L., Wacholder S., Tulinius H., Eyfjörd J. E. Population-based study of risk of breast cancer in carriers of BRCA2 mutation. Lancet. 1998 Oct 24;352(9137):1337–1339. doi: 10.1016/s0140-6736(98)03300-5. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES