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Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1998 Aug;89(8):842–848. doi: 10.1111/j.1349-7006.1998.tb00638.x

Somatic Mutations of the PTEN/MMAC1 Gene in Fifteen Japanese Endometrial Cancers: Evidence for Inactivation of Both Alleles

Keisuke Kurose 1,2, Koichi Bando 1, Koichi Fukino 1, Yuichi Sugisaki 3, Tsutomu Araki 2, Mitsuru Emi 1,✉
PMCID: PMC5921910  PMID: 9765621

Abstract

Loss of heterozygosity (LOH) of chromosome 10q is observed in approximately 40% of endometrial cancers. Mutations in PTEN/MMAC1, a gene recently isolated from the 10q23 region, are responsible for two dominantly inherited neoplastic syndromes, Cowden disease and Bannayan‐Zonana syndrome. Somatic mutations of this gene have also been detected in sporadic cancers of the brain, prostate and breast. To investigate the potential role of this putative tumor suppressor gene in endometrial carcinogenesis as well, we examined 46 primary endometrial cancers for LOH at the 10q23 region, and for mutations in the entire coding region and exon‐intron boundaries of the PTEN/MMAC1 gene. LOH was identified in half of the 38 informative cases, and subtle somatic mutations were detected in 15 tumors (33%). Our results suggest that of the genes studied so far in endometrial carcinomas, PTEN/MMAC1 is the most commonly mutated one, and that inactivation of both copies by allelic loss and/or mutation, a pattern that defines genes as “tumor suppressors,'’contributes to tumorigenesis in endometrial cancers.

Keywords: key words, PTEN/MMAC1, Endometrial cancer, Tumor suppressor gene, Chromosome 10q

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REFERENCES

  • 1. ) Parker , S. L. , Tong , T. , Bolden , S. and Wingo , P. A.Cancer statistics . CA Cancer J. Clin. , 46 , 5 – 27 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 2. ) Weinberg , R. A.Tumor suppressor genes . Science , 254 , 1138 – 1146 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 3. ) Nakamura , Y.Multi‐step carcinogenesis of colorectal cancer . Jpn. J. Hum. Genet. , 38 , 23 ( 1993. ). [Google Scholar]
  • 4. ) Knudson , A. G.Antioncogenes and human cancer . Proc. Natl. Acad. Sci. USA , 90 , 10914 – 10921 ( 1993. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5. ) Nakamura , Y.Application of DNA markers to clinical genetics . Jpn. J. Hum. Genet. , 41 , 1 – 10 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 6. ) Yanase , T.Human genetics: past, present, and future . Jpn. J. Hum. Genet. , 42 , 265 – 316 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 7. ) Peltomaki , P. , Lothe , R. A. , Aaltonen , L. A. , Pylkkanen , L. , Nystrom‐Lahti , M. , Seruca , R. , David , L. , Holm , R. , Ryberg , D. , Haugen , A. , Brogger , A. , Borresen , A.‐L. and de la Chapelle , A.Microsatellite instability is associated with tumors that characterize the hereditary non‐polyposis colorectal carcinoma syndrome . Cancer Res. , 53 , 5853 – 5855 ( 1993. ). [PubMed] [Google Scholar]
  • 8. ) Burks , R. T. , Kessis , T. D. , Cho , K. R. and Hedrick , L.Microsatellite instability in endometrial carcinoma . Oncogene , 9 , 1163 – 1166 ( 1994. ). [PubMed] [Google Scholar]
  • 9. ) Risinger , J. I. , Berchuck , A. , Kohler , M. F. , Watson , P. , Lynch , H. T. and Boyd , J.Genetic instability of microsatellites in endometrial carcinoma . Cancer Res. , 53 , 5100 – 5103 ( 1993. ). [PubMed] [Google Scholar]
  • 10. ) Enomoto , T. , Fujita , M. , Inoue , M. , Nomura , T. and Shroyer , K. R.Alteration of the p53 tumor suppressor gene and activation of c‐K‐ras‐2 protooncogene in endometrial adenocarcinoma from Colorado . Am. J. Clin. Pathol. , 103 , 224 – 230 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 11. ) Jones , M. H. , Koi , S. , Fujimoto , I. , Hasumi , K. , Kato , K. and Nakamura , Y.Allelotype of uterine cancer by analysis of RFLP and microsatellite polymorphisms: frequent loss of heterozygosity on chromosome arms 3p, 9q, 10q, and 17p . Genes Chromosom. Cancer , 9 , 119 – 123 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 12. ) Peiffer , S. L. , Herzog , T. J. , Tribune , D. J. , Mutch , D. G. , Gersell , D. J. and Goodfellow , P. J.Allelic loss of sequences from the long arm of chromosome 10 and replication errors in endometrial cancers . Cancer Res. , 55 , 1922 – 1926 ( 1995. ). [PubMed] [Google Scholar]
  • 13. ) Nagase , S. , Sato , S. , Tezuka , F. , Wada , Y. , Yajima , A. and Horii , A.Deletion mapping on chromosome 10q25–q26 in human endometrial cancer . Br. J. Cancer , 74 , 1979 – 1983 ( 1996. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14. ) Li , J. , Yen , C. , Liaw , D. , Podsypanina , K. , Bose , S. , Wang , S. I. , Puc , J. , Miliaresis , C. , Rodgers , L. , McCombie , R. , Bigner , S. H. , Giovanella , B. C. , Ittmann , M. , Tycko , B. , Hibshoosh , H. , Wigler , M. H. and Parsons , R.PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer . Science , 275 , 1943 – 1947 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 15. ) 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. , Frye , C. , Hu , R. , Swedlund , B. , Teng , D. H. and Tavtigian , S. V.Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers . Nat. Genet. , 15 , 356 – 362 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 16. ) 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. , Eng , C. and Parsons , R.Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome . Nat. Genet. , 16 , 64 – 67 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 17. ) Marsh , D. J. , Dahia , P. L. , Zheng , Z. , Liaw , D. , Parsons , R. , Gorlin , R. J. and Eng , C.Germline mutations in PTEN are present in Bannayan‐Zonana syndrome . Nat. Genet. , 16 , 333 – 334 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 18. ) Myers , M. P. , Stolarov , J. P. , Eng , C. , Li , J. , Wang , S. I. , Wigler , M. H. , Parsons , R. and Tonks , N. K.P‐TEN, the tumor suppressor from human chromosome 10q23, is a dual‐specificity phosphatase . Proc. Natl. Acad. Sci. USA , 94 , 9052 – 9057 ( 1997. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19. ) Sato , T. , Tanigami , A. , Yamakawa , K. , Akiyama , F. , Kasumi , F. , Sakamoto , G. and Nakamura , Y.Allelotype of breast cancer: cumulative allele losses promote tumor progression in primary breast cancer . Cancer Res. , 50 , 7184 – 7189 ( 1990. ). [PubMed] [Google Scholar]
  • 20. ) Scully , R. E. , Poulson , H. and Sobin , L. H.“International Histological Classification and Histologic Typing of Female Genital Tract Tumors” ( 1994. ). Springer‐Verlag; , Berlin . [Google Scholar]
  • 21. ) International Federation of Gynecology and Obstetrics . FIGO Stages, 1988 Revision . Gynecol. Oncol. , 35 , 125 – 127 ( 1989. ). [Google Scholar]
  • 22. ) Iida , A. , Isobe , R. , Yoshimoto , M. , Kasumi , F. , Nakamura , Y. and Emi , M.Localization of a breast cancer tumour‐suppressor gene to a 3‐cM interval within chromosomal region 16q22 . Br. J. Cancer , 75 , 264 – 267 ( 1997. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23. ) Orita , M. , Suzuki , Y. , Sekiya , T. and Hayashi , K.Rapid and sensitive detection of point mutations and DNA polymorphisms using the polymerase chain reaction . Genomics , 5 , 874 – 879 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 24. ) Tashiro , H. , Blazes , M. S. , Wu , R. , Cho , K. R. , Bose , S. , Wang , S. I. , Li , J. , Parsons , R. and Ellenson , L. H.Mutations in PTEN are frequent in endometrial carcinoma but rare in other common gynecological malignancies . Cancer Res. , 57 , 3935 – 3940 ( 1997. ). [PubMed] [Google Scholar]
  • 25. ) Risinger , J. I. , Hayes , A. K. , Berchuck , A. and Barrett , J. C.PTEN/MMAC1 mutations in endometrial cancers . Cancer Res. , 57 , 4736 – 4738 ( 1997. ). [PubMed] [Google Scholar]
  • 26. ) Rasheed , B. K. , Stenzel , T. T. , McLendon , R. E. , Parsons , R. , Friedman , A. H. , Friedman , H. S. , Bigner , D. D. and Bigner , S. H.PTEN gene mutations are seen in high‐grade but not in low‐grade gliomas . Cancer Res. , 57 , 4187 – 4190 ( 1997. ). [PubMed] [Google Scholar]
  • 27. ) Wang , S. I. , Puc , J. , Li , J. , Bruce , J. N. , Cairns , P. , Sidransky , D. and Parsons , R.Somatic mutations of PTEN in glioblastoma multiforme . Cancer Res. , 57 , 4183 – 4186 ( 1997. ). [PubMed] [Google Scholar]
  • 28. ) Marsh , D. J. , Coulon , V. , Lunetta , K. L. , Rocca‐Serra , P. , Dahia , P. L. , Zheng , Z. , Liaw , D. , Caron , S. , Duboue , B. , Lin , A. Y. , Richardson , A. L. , Bonnetblanc , J. M. , Bressieux , J. M. , Cabarrot‐Moreau , A. , Chompret , A. , Demange , L. , Eeles , R. A. , Yahanda , A. M. , Fearon , E. R. , Fricker , J. P. , Gorlin , R. J. , Hodgson , S. V. , Huson , S. , Lacombe , D. , LePrat , F. , Odent , S. , Toulouse , C. , Olopade , O. I. , Sobol , H. , Tishler , S. , Woods , C. G. , Robinson , B. G. , Weber , H. C. , Parsons , R. , Peacocke , M. , Longy , M. and Eng , C.Mutation spectrum and genotype‐phenotype analyses in Cowden disease and Bannayan‐Zonana syndrome, two hamartoma syndromes with germline PTEN mutation . Hum. Mol. Genet. , 7 , 507 – 515 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 29. ) Knudson , A. G.Mutation and cancer: statistical study of retinoblastoma . Proc. Natl. Acad. Sci. USA , 68 , 820 – 823 ( 1971. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30. ) Hashimoto , T. , Takahashi , R. , Yandell , D. W. , Xu , H. J. , Hu , S. X. , Gunnell , S. and Benedict , W. F.Characterization of intragenic deletions in two sporadic germinal mutation cases of retinoblastoma resulting in abnormal gene expression . Oncogene , 6 , 463 – 469 ( 1991. ). [PubMed] [Google Scholar]
  • 31. ) Zbar , B.Von Hippel‐Lindau disease and sporadic renal cell carcinoma . Cancer Surv. , 25 , 219 – 232 ( 1995. ). [PubMed] [Google Scholar]
  • 32. ) Little , M. and Wells , C.A clinical overview of WT1 gene mutations . Hum. Mutat. , 9 , 209 – 225 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 33. ) Rhei , E. , Kang , L. , Bogomolniy , F. , Federici , M. G. , Borgen , P. I. and Boyd , J.Mutation analysis of the putative tumor suppressor gene PTEN/MMAC1 in primary breast carcinomas . Cancer Res. , 57 , 3657 – 3659 ( 1997. ). [PubMed] [Google Scholar]
  • 34. ) Dahia , P. L. , Marsh , D. J. , Zheng , Z. , Zedenius , J. , Komminoth , P. , Frisk , T. , Wallin , G. , Parsons , R. , Longy , M. , Larsson , C. and Eng , C.Somatic deletions and mutations in the Cowden disease gene, PTEN, in sporadic thyroid tumors . Cancer Res. , 57 , 4710 – 4713 ( 1997. ). [PubMed] [Google Scholar]
  • 35. ) Ueda , K. , Nishijima , M. , Inui , H. , Watatani , M. , Yayoi , E. , Okamura , J. , Yasutomi , M. , Nakamura , Y. and Miyoshi , Y.Infrequent mutations in the PTEN/MMAC1 gene among primary breast cancers . Jpn. J. Cancer Res. , 89 , 17 – 21 ( 1998. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36. ) Beaudet , A. L. and Tsui , L.A suggested nomenclature for designating mutations . Hum. Mutat. , 2 , 245 – 248 ( 1993. ). [DOI] [PubMed] [Google Scholar]

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