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. 1997 Nov;61(5):1036–1043. doi: 10.1086/301607

The role of MMAC1 mutations in early-onset breast cancer: causative in association with Cowden syndrome and excluded in BRCA1-negative cases.

H C Tsou 1, D H Teng 1, X L Ping 1, V Brancolini 1, T Davis 1, R Hu 1, X X Xie 1, A C Gruener 1, C A Schrager 1, A M Christiano 1, C Eng 1, P Steck 1, J Ott 1, S V Tavtigian 1, M Peacocke 1
PMCID: PMC1716044  PMID: 9345101

Abstract

Cowden syndrome (CS) is an autosomal dominant disorder associated with the development of hamartomas and benign tumors in a variety of tissues, including the skin, thyroid, breast, endometrium, and brain. It has been suggested that women with CS are at increased risk for breast cancer. A locus for CS was recently defined on chromosome 10 in 12 families, resulting in the identification of the CS critical interval, between the markers D10S215 and D10S541. More recently, affected individuals in four families with CS have been shown to have germ-line mutations in a gene known as "PTEN," or "MMAC1," which is located in the CS critical interval on chromosome 10. In this study, we report three novel MMAC1 mutations in CS and demonstrate that MMAC1 mutations are associated with CS and breast cancer. Furthermore, we also show that certain families and individuals with CS do not have mutations in the coding sequence of MMAC1. Finally, we did not detect MMAC1 mutations in a subpopulation of individuals with early-onset breast cancer, suggesting that germ-line mutations in this gene do not appear to be common in this group.

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Selected References

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  1. Albrecht S., Haber R. M., Goodman J. C., Duvic M. Cowden syndrome and Lhermitte-Duclos disease. Cancer. 1992 Aug 15;70(4):869–876. doi: 10.1002/1097-0142(19920815)70:4<869::aid-cncr2820700424>3.0.co;2-e. [DOI] [PubMed] [Google Scholar]
  2. Brownstein M. H., Mehregan A. H., Bilowski J. B. Trichilemmomas in Cowden's disease. JAMA. 1977 Jul 4;238(1):26–26. [PubMed] [Google Scholar]
  3. Brownstein M. H., Wolf M., Bikowski J. B. Cowden's disease: a cutaneous marker of breast cancer. Cancer. 1978 Jun;41(6):2393–2398. doi: 10.1002/1097-0142(197806)41:6<2393::aid-cncr2820410644>3.0.co;2-k. [DOI] [PubMed] [Google Scholar]
  4. Claus E. B., Risch N. J., Thompson W. D. Age at onset as an indicator of familial risk of breast cancer. Am J Epidemiol. 1990 Jun;131(6):961–972. doi: 10.1093/oxfordjournals.aje.a115616. [DOI] [PubMed] [Google Scholar]
  5. Ford D., Easton D. F., Peto J. Estimates of the gene frequency of BRCA1 and its contribution to breast and ovarian cancer incidence. Am J Hum Genet. 1995 Dec;57(6):1457–1462. [PMC free article] [PubMed] [Google Scholar]
  6. Fornander T., Rutqvist L. E., Cedermark B., Glas U., Mattsson A., Silfverswärd C., Skoog L., Somell A., Theve T., Wilking N. Adjuvant tamoxifen in early breast cancer: occurrence of new primary cancers. Lancet. 1989 Jan 21;1(8630):117–120. doi: 10.1016/s0140-6736(89)91141-0. [DOI] [PubMed] [Google Scholar]
  7. Haines J. L., Short M. P., Kwiatkowski D. J., Jewell A., Andermann E., Bejjani B., Yang C. H., Gusella J. F., Amos J. A. Localization of one gene for tuberous sclerosis within 9q32-9q34, and further evidence for heterogeneity. Am J Hum Genet. 1991 Oct;49(4):764–772. [PMC free article] [PubMed] [Google Scholar]
  8. Kandt R. S., Haines J. L., Smith M., Northrup H., Gardner R. J., Short M. P., Dumars K., Roach E. S., Steingold S., Wall S. Linkage of an important gene locus for tuberous sclerosis to a chromosome 16 marker for polycystic kidney disease. Nat Genet. 1992 Sep;2(1):37–41. doi: 10.1038/ng0992-37. [DOI] [PubMed] [Google Scholar]
  9. Kruglyak L., Daly M. J., Reeve-Daly M. P., Lander E. S. Parametric and nonparametric linkage analysis: a unified multipoint approach. Am J Hum Genet. 1996 Jun;58(6):1347–1363. [PMC free article] [PubMed] [Google Scholar]
  10. LLOYD K. M., 2nd, DENNIS M. Cowden's disease. A possible new symptom complex with multiple system involvement. Ann Intern Med. 1963 Jan;58:136–142. doi: 10.7326/0003-4819-58-1-136. [DOI] [PubMed] [Google Scholar]
  11. Lathrop G. M., Lalouel J. M., Julier C., Ott J. Strategies for multilocus linkage analysis in humans. Proc Natl Acad Sci U S A. 1984 Jun;81(11):3443–3446. doi: 10.1073/pnas.81.11.3443. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Li D. M., Sun H. TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta. Cancer Res. 1997 Jun 1;57(11):2124–2129. [PubMed] [Google Scholar]
  13. Li J., Yen C., Liaw D., Podsypanina K., Bose S., Wang S. I., Puc J., Miliaresis C., Rodgers L., McCombie R. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science. 1997 Mar 28;275(5308):1943–1947. doi: 10.1126/science.275.5308.1943. [DOI] [PubMed] [Google Scholar]
  14. Liaw D., Marsh D. J., Li J., Dahia P. L., Wang S. I., Zheng Z., Bose S., Call K. M., Tsou H. C., Peacocke M. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet. 1997 May;16(1):64–67. doi: 10.1038/ng0597-64. [DOI] [PubMed] [Google Scholar]
  15. Miki Y., Swensen J., Shattuck-Eidens D., Futreal P. A., Harshman K., Tavtigian S., Liu Q., Cochran C., Bennett L. M., Ding W. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994 Oct 7;266(5182):66–71. doi: 10.1126/science.7545954. [DOI] [PubMed] [Google Scholar]
  16. Starink T. M., van der Veen J. P., Arwert F., de Waal L. P., de Lange G. G., Gille J. J., Eriksson A. W. The Cowden syndrome: a clinical and genetic study in 21 patients. Clin Genet. 1986 Mar;29(3):222–233. doi: 10.1111/j.1399-0004.1986.tb00816.x. [DOI] [PubMed] [Google Scholar]
  17. Steck P. A., Pershouse M. A., Jasser S. A., Yung W. K., Lin H., Ligon A. H., Langford L. A., Baumgard M. L., Hattier T., Davis T. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet. 1997 Apr;15(4):356–362. doi: 10.1038/ng0497-356. [DOI] [PubMed] [Google Scholar]
  18. Tavtigian S. V., Simard J., Rommens J., Couch F., Shattuck-Eidens D., Neuhausen S., Merajver S., Thorlacius S., Offit K., Stoppa-Lyonnet D. The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds. Nat Genet. 1996 Mar;12(3):333–337. doi: 10.1038/ng0396-333. [DOI] [PubMed] [Google Scholar]
  19. Walton B. J., Morain W. D., Baughman R. D., Jordan A., Crichlow R. W. Cowden's disease: a further indication for prophylactic mastectomy. Surgery. 1986 Jan;99(1):82–86. [PubMed] [Google Scholar]
  20. Weary P. E., Gorlin R. J., Gentry W. C., Jr, Comer J. E., Greer K. E. Multiple hamartoma syndrome (Cowden's disease). Arch Dermatol. 1972 Nov;106(5):682–690. [PubMed] [Google Scholar]
  21. Wooster R., Bignell G., Lancaster J., Swift S., Seal S., Mangion J., Collins N., Gregory S., Gumbs C., Micklem G. Identification of the breast cancer susceptibility gene BRCA2. Nature. 1995 Dec 21;378(6559):789–792. doi: 10.1038/378789a0. [DOI] [PubMed] [Google Scholar]

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