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. 1992 May;89(5):1517–1522. doi: 10.1172/JCI115743

Ret oncogene activation in human thyroid neoplasms is restricted to the papillary cancer subtype.

M Santoro 1, F Carlomagno 1, I D Hay 1, M A Herrmann 1, M Grieco 1, R Melillo 1, M A Pierotti 1, I Bongarzone 1, G Della Porta 1, N Berger 1, et al.
PMCID: PMC443023  PMID: 1569189

Abstract

We have recently reported the activation of a new oncogene in human papillary thyroid carcinomas. This oncogene, papillary thyroid carcinoma (PTC), is a novel rearranged version of the ret tyrosine-kinase protooncogene. Thyroid neoplasms include a broad spectrum of malignant tumors, ranging from well-differentiated tumors to undifferentiated anaplastic carcinomas. To determine the frequency of ret oncogene activation, we analyzed 286 cases of human thyroid tumors of diverse histologic types. We found the presence of an activated form of the ret oncogene in 33 (19%) of 177 papillary carcinomas. By contrast, none of the other 109 thyroid tumors, which included 37 follicular, 15 anaplastic, and 18 medullary carcinomas, and 34 benign lesions, showed ret activation.

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Selected References

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

  1. Almoguera C., Shibata D., Forrester K., Martin J., Arnheim N., Perucho M. Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell. 1988 May 20;53(4):549–554. doi: 10.1016/0092-8674(88)90571-5. [DOI] [PubMed] [Google Scholar]
  2. Bishop J. M. The molecular genetics of cancer. Science. 1987 Jan 16;235(4786):305–311. doi: 10.1126/science.3541204. [DOI] [PubMed] [Google Scholar]
  3. Bongarzone I., Pierotti M. A., Monzini N., Mondellini P., Manenti G., Donghi R., Pilotti S., Grieco M., Santoro M., Fusco A. High frequency of activation of tyrosine kinase oncogenes in human papillary thyroid carcinoma. Oncogene. 1989 Dec;4(12):1457–1462. [PubMed] [Google Scholar]
  4. Bos J. L., Fearon E. R., Hamilton S. R., Verlaan-de Vries M., van Boom J. H., van der Eb A. J., Vogelstein B. Prevalence of ras gene mutations in human colorectal cancers. 1987 May 28-Jun 3Nature. 327(6120):293–297. doi: 10.1038/327293a0. [DOI] [PubMed] [Google Scholar]
  5. Farr C. J., Saiki R. K., Erlich H. A., McCormick F., Marshall C. J. Analysis of RAS gene mutations in acute myeloid leukemia by polymerase chain reaction and oligonucleotide probes. Proc Natl Acad Sci U S A. 1988 Mar;85(5):1629–1633. doi: 10.1073/pnas.85.5.1629. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Fusco A., Grieco M., Santoro M., Berlingieri M. T., Pilotti S., Pierotti M. A., Della Porta G., Vecchio G. A new oncogene in human thyroid papillary carcinomas and their lymph-nodal metastases. Nature. 1987 Jul 9;328(6126):170–172. doi: 10.1038/328170a0. [DOI] [PubMed] [Google Scholar]
  7. Grieco M., Santoro M., Berlingieri M. T., Melillo R. M., Donghi R., Bongarzone I., Pierotti M. A., Della Porta G., Fusco A., Vecchio G. PTC is a novel rearranged form of the ret proto-oncogene and is frequently detected in vivo in human thyroid papillary carcinomas. Cell. 1990 Feb 23;60(4):557–563. doi: 10.1016/0092-8674(90)90659-3. [DOI] [PubMed] [Google Scholar]
  8. Herrmann M. A., Hay I. D., Bartelt D. H., Jr, Ritland S. R., Dahl R. J., Grant C. S., Jenkins R. B. Cytogenetic and molecular genetic studies of follicular and papillary thyroid cancers. J Clin Invest. 1991 Nov;88(5):1596–1604. doi: 10.1172/JCI115472. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Ishizaka Y., Itoh F., Tahira T., Ikeda I., Ogura T., Sugimura T., Nagao M. Presence of aberrant transcripts of ret proto-oncogene in a human papillary thyroid carcinoma cell line. Jpn J Cancer Res. 1989 Dec;80(12):1149–1152. doi: 10.1111/j.1349-7006.1989.tb01645.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Ishizaka Y., Itoh F., Tahira T., Ikeda I., Sugimura T., Tucker J., Fertitta A., Carrano A. V., Nagao M. Human ret proto-oncogene mapped to chromosome 10q11.2. Oncogene. 1989 Dec;4(12):1519–1521. [PubMed] [Google Scholar]
  11. Ishizaka Y., Kobayashi S., Ushijima T., Hirohashi S., Sugimura T., Nagao M. Detection of retTPC/PTC transcripts in thyroid adenomas and adenomatous goiter by an RT-PCR method. Oncogene. 1991 Sep;6(9):1667–1672. [PubMed] [Google Scholar]
  12. Ishizaka Y., Ochiai M., Tahira T., Sugimura T., Nagao M. Activation of the ret-II oncogene without a sequence encoding a transmembrane domain and transforming activity of two ret-II oncogene products differing in carboxy-termini due to alternative splicing. Oncogene. 1989 Jun;4(6):789–794. [PubMed] [Google Scholar]
  13. Ishizaka Y., Ushijima T., Sugimura T., Nagao M. cDNA cloning and characterization of ret activated in a human papillary thyroid carcinoma cell line. Biochem Biophys Res Commun. 1990 Apr 30;168(2):402–408. doi: 10.1016/0006-291x(90)92335-w. [DOI] [PubMed] [Google Scholar]
  14. Jenkins R. B., Hay I. D., Herath J. F., Schultz C. G., Spurbeck J. L., Grant C. S., Goellner J. R., Dewald G. W. Frequent occurrence of cytogenetic abnormalities in sporadic nonmedullary thyroid carcinoma. Cancer. 1990 Sep 15;66(6):1213–1220. doi: 10.1002/1097-0142(19900915)66:6<1213::aid-cncr2820660622>3.0.co;2-9. [DOI] [PubMed] [Google Scholar]
  15. Klein G. The approaching era of the tumor suppressor genes. Science. 1987 Dec 11;238(4833):1539–1545. doi: 10.1126/science.3317834. [DOI] [PubMed] [Google Scholar]
  16. Koda T. [ret gene from a human stomach cancer]. Hokkaido Igaku Zasshi. 1988 Nov;63(6):913–924. [PubMed] [Google Scholar]
  17. Lemoine N. R., Mayall E. S., Wyllie F. S., Farr C. J., Hughes D., Padua R. A., Thurston V., Williams E. D., Wynford-Thomas D. Activated ras oncogenes in human thyroid cancers. Cancer Res. 1988 Aug 15;48(16):4459–4463. [PubMed] [Google Scholar]
  18. Lemoine N. R., Mayall E. S., Wyllie F. S., Williams E. D., Goyns M., Stringer B., Wynford-Thomas D. High frequency of ras oncogene activation in all stages of human thyroid tumorigenesis. Oncogene. 1989 Feb;4(2):159–164. [PubMed] [Google Scholar]
  19. Namba H., Gutman R. A., Matsuo K., Alvarez A., Fagin J. A. H-ras protooncogene mutations in human thyroid neoplasms. J Clin Endocrinol Metab. 1990 Jul;71(1):223–229. doi: 10.1210/jcem-71-1-223. [DOI] [PubMed] [Google Scholar]
  20. Namba H., Rubin S. A., Fagin J. A. Point mutations of ras oncogenes are an early event in thyroid tumorigenesis. Mol Endocrinol. 1990 Oct;4(10):1474–1479. doi: 10.1210/mend-4-10-1474. [DOI] [PubMed] [Google Scholar]
  21. Pierotti M. A., Santoro M., Jenkins R. B., Sozzi G., Bongarzone I., Grieco M., Monzini N., Miozzo M., Herrmann M. A., Fusco A. Characterization of an inversion on the long arm of chromosome 10 juxtaposing D10S170 and RET and creating the oncogenic sequence RET/PTC. Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1616–1620. doi: 10.1073/pnas.89.5.1616. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Rodenhuis S., Slebos R. J., Boot A. J., Evers S. G., Mooi W. J., Wagenaar S. S., van Bodegom P. C., Bos J. L. Incidence and possible clinical significance of K-ras oncogene activation in adenocarcinoma of the human lung. Cancer Res. 1988 Oct 15;48(20):5738–5741. [PubMed] [Google Scholar]
  23. Santoro M., Rosati R., Grieco M., Berlingieri M. T., D'Amato G. L., de Franciscis V., Fusco A. The ret proto-oncogene is consistently expressed in human pheochromocytomas and thyroid medullary carcinomas. Oncogene. 1990 Oct;5(10):1595–1598. [PubMed] [Google Scholar]
  24. Seeger R. C., Brodeur G. M., Sather H., Dalton A., Siegel S. E., Wong K. Y., Hammond D. Association of multiple copies of the N-myc oncogene with rapid progression of neuroblastomas. N Engl J Med. 1985 Oct 31;313(18):1111–1116. doi: 10.1056/NEJM198510313131802. [DOI] [PubMed] [Google Scholar]
  25. Shi Y. F., Zou M. J., Schmidt H., Juhasz F., Stensky V., Robb D., Farid N. R. High rates of ras codon 61 mutation in thyroid tumors in an iodide-deficient area. Cancer Res. 1991 May 15;51(10):2690–2693. [PubMed] [Google Scholar]
  26. Slamon D. J., Godolphin W., Jones L. A., Holt J. A., Wong S. G., Keith D. E., Levin W. J., Stuart S. G., Udove J., Ullrich A. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989 May 12;244(4905):707–712. doi: 10.1126/science.2470152. [DOI] [PubMed] [Google Scholar]
  27. Sozzi G., Pierotti M. A., Miozzo M., Donghi R., Radice P., De Benedetti V., Grieco M., Santoro M., Fusco A., Vecchio G. Refined localization to contiguous regions on chromosome 10q of the two genes (H4 and RET) that form the oncogenic sequence PTC. Oncogene. 1991 Feb;6(2):339–342. [PubMed] [Google Scholar]
  28. Suarez H. G., du Villard J. A., Caillou B., Schlumberger M., Parmentier C., Monier R. gsp mutations in human thyroid tumours. Oncogene. 1991 Apr;6(4):677–679. [PubMed] [Google Scholar]
  29. Suarez H. G., du Villard J. A., Severino M., Caillou B., Schlumberger M., Tubiana M., Parmentier C., Monier R. Presence of mutations in all three ras genes in human thyroid tumors. Oncogene. 1990 Apr;5(4):565–570. [PubMed] [Google Scholar]
  30. Takahashi M., Buma Y., Hiai H. Isolation of ret proto-oncogene cDNA with an amino-terminal signal sequence. Oncogene. 1989 Jun;4(6):805–806. [PubMed] [Google Scholar]
  31. Takahashi M., Buma Y., Iwamoto T., Inaguma Y., Ikeda H., Hiai H. Cloning and expression of the ret proto-oncogene encoding a tyrosine kinase with two potential transmembrane domains. Oncogene. 1988 Nov;3(5):571–578. [PubMed] [Google Scholar]
  32. Takahashi M., Cooper G. M. ret transforming gene encodes a fusion protein homologous to tyrosine kinases. Mol Cell Biol. 1987 Apr;7(4):1378–1385. doi: 10.1128/mcb.7.4.1378. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Takahashi M., Inaguma Y., Hiai H., Hirose F. Developmentally regulated expression of a human "finger"-containing gene encoded by the 5' half of the ret transforming gene. Mol Cell Biol. 1988 Apr;8(4):1853–1856. doi: 10.1128/mcb.8.4.1853. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Weinberg R. A. Oncogenes, antioncogenes, and the molecular bases of multistep carcinogenesis. Cancer Res. 1989 Jul 15;49(14):3713–3721. [PubMed] [Google Scholar]
  35. Williams E. D. Thyroid cancer: pathologic and natural history. Recent Results Cancer Res. 1980;73:47–55. doi: 10.1007/978-3-642-81325-2_5. [DOI] [PubMed] [Google Scholar]
  36. Wright P. A., Williams E. D., Lemoine N. R., Wynford-Thomas D. Radiation-associated and 'spontaneous' human thyroid carcinomas show a different pattern of ras oncogene mutation. Oncogene. 1991 Mar;6(3):471–473. [PubMed] [Google Scholar]

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