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Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1995 Aug;86(8):737–742. doi: 10.1111/j.1349-7006.1995.tb02462.x

Point Mutations of ras and Gsα Subunit Genes in Thyroid Tumors

Hidetaka Horie 1,✉, Yutaka Yokogoshi 1, Masaru Tsuyuguchi 2, Shiro Saito 1
PMCID: PMC5920910  PMID: 7559096

Abstract

We studied 43 thyroid tumors including 5 adenomatous goiters, 7 follicular adenomas, 22 papillary carcinomas, and 9 medullary carcinomas with regard to the presence of point mutations in the genes of Gs alpha subunit (Gsα), Gi2 alpha subunit (Gi2α), H‐ras, K‐ras, and N‐ras by a polymerase chain reaction‐direct sequencing method. An adenomatous goiter and a follicular adenoma showed double mutations at codon 227 and 231, and 4 papillary carcinomas showed mutation at codon 231 of the Gsα gene. An adenomatous goiter, a follicular adenoma, and a papillary carcinoma showed a missense mutation in codon 13 of the K‐ras gene. There were no such missense mutations of these G‐protein or ras genes in medullary carcinomas. These data indicate that the genetic events involved in the oncogenesis of parafollicular C‐cells are different from those of thyroid follicular cells, in which missense mutations of Gsα and ras genes seem to play important roles in tumorigenesis.

Keywords: Gsα, Gi2α, ras, Thyroid tumor

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REFERENCES

  • 1. ) Rojeski , M. T. and Gharib , H.Nodular thyroid disease. Evaluation and management . N. Engl. J. Med. , 313 , 428 – 436 ( 1985. ). [DOI] [PubMed] [Google Scholar]
  • 2. ) Mortensen , J. D. , Woolner , L. B. and Bennett , W. A.Gross and microscopic findings in clinically normal thyroid glands . J. Clin. Endocrinol. Metab. , 15 , 1270 – 1280 ( 1955. ). [DOI] [PubMed] [Google Scholar]
  • 3. ) Uribe , M. , Grimes , M. , Fenoglio‐Preiser , C. M. and Feind , C.Medullary carcinoma of the thyroid gland. Clinical, pathological, and immunohistochemical features with review of the literature . Am. J. Surg. Pathol. , 9 , 577 – 594 ( 1985. ). [DOI] [PubMed] [Google Scholar]
  • 4. ) Parker , L. N. , Belsky , J. L. , Yamamoto , T. , Kawamoto , S. and Keehn , R. J.Hiroshima shi, Japan. Thyroid carcinoma after exposure to atomic radiation. A continuing survey of a fixed population, Hiroshima and Nagasaki, 1958–1971 . Ann. Intern. Med. , 80 , 600 – 604 ( 1974. ). [DOI] [PubMed] [Google Scholar]
  • 5. ) Belfiore , A. , La Rosa , G. L. , Padova , G. , Sava , L. , Ippolito , O. and Vigneri , R.The frequency of cold thyroid nodules and thyroid malignancies in patients from an iodine‐deficient area . Cancer , 60 , 3096 – 3102 ( 1987. ). [DOI] [PubMed] [Google Scholar]
  • 6. ) Thomas , G. A. and Williams , E. D.Evidence for and possible mechanisms of non‐genotoxic carcinogenesis in the rodent thyroid . Mutat. Res. , 248 , 357 – 370 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 7. ) Frauman , A. G. and Moses , A. C.Oncogenes and growth factors in thyroid carcinogenesis . Endocrinol. Metab. Clin. North Am. , 19 , 479 – 493 ( 1990. ). [PubMed] [Google Scholar]
  • 8. ) Fagin , J. A.Genetic basis of endocrine disease 3—molecular defects in thyroid gland neoplasia . J. Clin. Endocrinol. Metab. , 75 , 1398 – 1400 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 9. ) Smith , P. and Wynford‐Thomas , D.Control of thyroid follicular cell proliferation—cellular aspects . In “ Thyroid Tumors: Molecular Basis of Pathogenesis ,” ed. Wynford‐Thomas D. and Williams E. D. , pp. 66 – 90 ( 1984. ). Churchill Livingstone; , New York . [Google Scholar]
  • 10. ) Johnson , G. L. and Dhanasekaran , N.The G‐protein family and their interaction with receptors . Endocr. Rev. , 10 , 317 – 331 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 11. ) Maenhaut , C. , Roger , P. P. , Reuse , S. and Dumont , J. E.Activation of the cyclic AMP cascade as an oncogenic mechanism: the thyroid example . Biochimie , 73 , 29 – 36 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 12. ) Lyons , J. , Landis , C. A. , Harsh , G. , Vallar , L. , Grünewald , K. , Feichtinger , H. , Duh , Q.‐Y. , Clark , O. H. , Kawasaki , E. , Bourne , H. R. and McCormick , F.Two G protein oncogenes in human endocrine tumors . Science , 249 , 655 – 659 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 13. ) Hosoi , E. , Yokogoshi , Y. , Hosoi , E. , Horie , H. , Sano , T. , Yamada , S. and Saito , S.Analysis of the Gs α gene in growth hormone‐secreting pituitary adenomas by the polymerase chain reaction‐direct sequencing method using paraffin‐embedded tissues . Acta Endocrinol. , 129 , 301 – 306 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 14. ) Blenis , J.Signal transduction via the MAP kinases: proceed at your own RSK . Proc. Natl. Acad. Sci. USA , 90 , 5889 – 5892 ( 1993. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15. ) Crespo , P. , Xu , N. , Simonds , W. F. and Gutkind , J. S.Ras‐dependent activation of MAP kinase pathway mediated by G‐protein βγ subunits . Nature , 369 , 418 – 420 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 16. ) Herrman , M. A. , Hay , I. D. , Bartelt , D. H. , Jr. , Ritland , S. R. , Dahl , R. J. , Grand , C. S. and Jenkins , R. B.Cytogenetic and molecular genetic studies of follicular and papillary thyroid cancers . J. Clin. Invest. , 88 , 1596 – 1604 ( 1991. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17. ) Lemoine , N. R. , Mayall , E. S. , Wyllie , F. S. , Williams , E. D. , Goyns , M. , Stringer , B. and Wynford‐Thomas , D.High frequency of ras oncogene activation in all stages of human thyroid tumorigenesis . Oncogene , 4 , 159 – 164 ( 1989. ). [PubMed] [Google Scholar]
  • 18. ) Suarez , H. G. , Villard , J. A. , Severino , M. , Caillou , B. , Schlumberger , M. , Tubiana , M. , Parmentier , C. and Monier , R.Presence of mutations in all three ras genes in human thyroid tumors . Oncogene , 5 , 565 – 570 ( 1990. ). [PubMed] [Google Scholar]
  • 19. ) Shi , Y. , Zou , M. , Schmidt , H. , Juhasz , F. , Stensky , V. , Robb , D. and Farid , N. R.High rates of ras codon 61 mutation in thyroid tumors in an iodide‐deficient area . Cancer Res. , 51 , 2690 – 2693 ( 1991. ). [PubMed] [Google Scholar]
  • 20. ) Karga , H. , Lee , J.‐K. , Vickery , A. L. , Jr. , Thor , A. , Gaz , R. D. and Jameson , J. L.ras oncogene mutations in benign and malignant thyroid neoplasms . J. Clin. Endocrinol. Metab. , 73 , 832 – 836 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 21. ) Yoshimoto , K. , Iwahana , H. , Fukuda , A. , Sano , T. , Katsuragi , K. , Kinoshita , M. , Saito , S. and Itakura , M.ras mutations in endocrine tumors: mutation detection by polymerase chain reaction‐single strand conformation polymorphism . Jpn. J. Cancer Res. , 83 , 1057 – 1062 ( 1992. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22. ) O'Sullivan , C. , Barton , C. M. , Staddon , S. L. , Brown , C. L. and Lemoine , N. R.Activating point mutations of the gsp oncogene in human thyroid adenomas . Mol. Carcinog. , 4 , 345 – 349 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 23. ) Suarez , H. G. , Villard , J. A. , Caillou , B. , Schlumberger , M. , Parmentier , C. and Monier , R.gsp mutations in human thryoid tumors , Oncogene , 6 , 677 – 679 ( 1991. ). [PubMed] [Google Scholar]
  • 24. ) Matsuo , K. , Friedman , E. , Gejman , P. V. and Fagin , J. A.The thyrotropin receptor (TSH‐R) is not an oncogene for thyroid tumors: structural studies of the TSH‐R and the α‐subunit of Gs in human thyroid neoplasms . J. Clin. Endocrinol. Metab. , 76 , 1446 – 1451 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 25. ) Yoshimoto , K. , Iwahana , H. , Fukuda , A. , Sano , T. and Itakura , M.Rare mutations of the Gs alpha subunit gene in human endocrine tumors . Cancer , 72 , 1386 – 1393 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 26. ) Fagin , J. A. , Matsuo , K. , Karmakar , A. , Chen , D. L. , Tang , S.‐H. and Koeffler , H. P.High prevalence of mutations of the p53 gene in poorly differentiated human thyroid carcinomas . J. Clin. Invest. , 91 , 179 – 184 ( 1993. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27. ) Santoro , M. , Carlomagno , F. , Hay , I. D. , Herrmann , M. A. , Grieco , M. , Melillo , R. , Pierotti , M. A. , Bongarzone , I. , Porta , G. D. , Berger , N. , Peix , J. L. , Paulin , C. , Fabien , N. , Vecchio , G. , Jenkins , R. B. and Fusco , A.Ret oncogene activation in human thyroid neoplasms is restricted to the papillary cancer subtype . J. Clin. Invest. , 89 , 1517 – 1522 ( 1992. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28. ) Bongarzone , I. , Pierotti , M. A. , Monzini , N. , Mondellini , P. , Manenti , G. , Donghi , R. , Pilotti , S. , Grieco , M. , Santoro , M. , Fusco , A. , Vecchio , G. and Porta , G. D.High frequency activation of tyrosine kinase oncogenes in human papillary thyroid carcinoma . Oncogene , 4 , 1457 – 1462 ( 1989. ). [PubMed] [Google Scholar]
  • 29. ) Mulligan , L. M. , Eng , C. , Healey , C. S. , Clayton , D. , Kwok , J. B. J. , Gardner , E. , Ponder , M. A. , Frilling , A. , Jackson , C. E. , Lehnert , H. , Neumann , H. P. H. , Thibodeau , S. N. and Ponder , B. A. J.Specific mutations of the RET proto‐oncogene are related to disease phenotype in MEN 2A and FMTC . Nature Genet. , 6 , 70 – 74 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 30. ) Hofstra , R. M. W. , Landsvater , R. M. , Ceccherini , I. , Stulp , R. P. , Stelwagen , T. , Luo , Y. , Pasini , B. , Höppener , J. W. M. , van Amstel , H. K. P. , Romeo , G. , Lips , C. J. M. and Buys , C. H. C. M.Mutation in the RET protooncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma . Nature , 367 , 375 – 376 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 31. ) Hosoi , E. , Yokogoshi , Y. , Hosoi , E. , Yokoi , K. , Sano , T. and Saito , S.A pituitary specific point mutation of codon 201 of the Gsα gene in a pituitary adenoma of a patient with multiple endocrine neoplasia (MEN) type I . Endocrinol. Jpn. , 39 , 319 – 324 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 32. ) Stringer , B. M. , Rowson , J. M. , Parkar , M. H. , Seid , J. M. , Hearn , P. R. , Wynford‐Thomas , D. , Ingemansson , S. , Woodhouse , N. and Goyns , M. H.Detection of the H‐ras oncogene in human thyroid anaplastic carcinomas . Experientia , 45 , 372 – 376 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 33. ) Namba , H. , Matsuo , K. and Fagin , J. A.Clonal composition of benign and malignant human thyroid tumors . J. Clin. Invest. , 86 , 120 – 125 ( 1990. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34. ) Goretzki , P. E. , Lyons , J. , Stacy‐Phipps , S. , Rosenau , W. , Demeure , M. , Clark , O. H. , McCormick , F. , Röher , H.‐D. and Bourne , H. R.Mutational activation of ras and gsp oncogenes in differentiated thyroid cancer and their biological implications . World J. Surg. , 16 , 576 – 582 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 35. ) Edmonds , C. J. and Tellez , M.Hyperthyroidism and thyroid cancer . Clin. Endocrinol. , 28 , 253 – 259 ( 1988. ). [DOI] [PubMed] [Google Scholar]
  • 36. ) Nelkin , B. D. , de Bustros , A. C. , Mabry , M. and Baylin , S. B.The molecular biology of medullary thyroid carcinoma. A model for cancer development and progression . J. Am. Med. Assoc. , 261 , 3130 – 3135 ( 1989. ). [PubMed] [Google Scholar]
  • 37. ) Yang , K.‐P. , Castillo , S. G. , Nguyen , C. V. , Hickey , R. C. and Samaan , N. A.c‐myc, N‐myc, N‐ras and c‐erb‐B: lack of amplification or rearrangement in human medullary thyroid carcinoma and a derivative cell line . Anticancer Res. , 10 , 189 – 192 ( 1990. ). [PubMed] [Google Scholar]
  • 38. ) Moley , J. F. , Brother , M. B. , Wells , S. A. , Spengler , B. A. , Biedler , J. L. and Brodeur , G. M.Low frequency of ras gene mutations in neuroblastomas, pheochromocytomas, and medullary thyroid cancers . Cancer Res. , 51 , 1596 – 1599 ( 1991. ). [PubMed] [Google Scholar]
  • 39. ) Yana , I. , Nakamura , T. , Shin , E. , Karakawa , K. , Kurahashi , H. , Kurita , Y. , Kobayashi , T. , Mori , T. , Nishisho , I. and Takai , S.Inactivation of the p53 gene is not required for tumorigenesis of medullary thyroid carcinoma or pheochromocytoma . Jpn. J. Cancer Res. , 83 , 1113 – 1116 ( 1992. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40. ) Nakagawa , T. , Mabry , M. , de Bustros , A. , Ihle , J. N. , Nelkin , B. D. and Baylin , S. B.Introduction of v‐Ha‐ras oncogene induces differentiation of cultured human medullary thyroid carcinoma cells . Proc. Natl. Acad. Sci. USA , 84 , 5923 – 5927 ( 1987. ). [DOI] [PMC free article] [PubMed] [Google Scholar]

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