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. 1992 Dec;83(12):1293–1298. doi: 10.1111/j.1349-7006.1992.tb02761.x

p53 Gene Mutations Associated with Anaplastic Transformation of Human Thyroid Carcinomas

Tsutomu Nakamura 1, Ikuo Yana 1,2, Tetsuro Kobayashi 2, Eisei Shin 2, Katsu Karakawa 2, Shoichi Fujita 2, Akihiro Miya 2, Takesada Mori 2, Isamu Nishisho 1,✉, Shin‐ichiro Takai 1
PMCID: PMC5918745  PMID: 1483945

Abstract

Anaplastic carcinoma of the thyroid gland, which is one of the most aggressive, malignant tumors in humans, is considered to originate from preexisting differentiated thyroid cancer. To define the genetic alterations associated with such progression, we examined nine cases of anaplastic thyroid carcinoma for mutation in exons 4–9 of the p53 tumor suppressor gene. Preliminary screening for mutation by RNase protection analysis demonstrated that two out of nine anaplastic carcinomas contained sequence alterations in the p53 gene. Subsequent DNA sequencing identified the mutated nucleotides in these two cases; one was a nonsense mutation at codon 165, and the other was a single‐base deletion at codon 176 resulting in the creation of a stop codon downstream due to frameshift. The fact that no mutations were detected in coexisting foci of papillary carcinomas from the same patients shows that these mutations of the p53 gene occurred after development of papillary carcinomas. These results suggest that p53 gene mutation triggers the progression from differentiated into anaplastic carcinoma in the human thyroid gland.

Keywords: p53 gene, Anaplastic thyroid carcinoma, Progression, RNase protection analysis

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REFERENCES

  • 1. ) Venkatesh , Y. S. S. , Ordonez , N. G. , Schultz , P. N. , Hickey , R. C. , Goepfert , H. and Samaan , N. A.Anaplastic carcinoma of the thyroid: a clinicopathological study of 121 cases . Cancer , 66 , 321 – 330 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 2. ) Jereb , B. , Stjernswart , J. and Lowhagen , T.Anaplastic giant‐cell carcinoma of the thyroid: a study of treatment and prognosis . Cancer , 35 , 1293 – 1295 ( 1975. ). [DOI] [PubMed] [Google Scholar]
  • 3. ) Aldinger , K. A. , Samaan , N. A. , Ibanez , M. and Hill , C. S. , Jr.Anaplastic carcinoma of the thyroid: a review of 84 cases of spindle and giant cell carcinoma of the thyroid . Cancer , 41 , 2267 – 2275 ( 1978. ). [DOI] [PubMed] [Google Scholar]
  • 4. ) Nishiyama , R. H. , Dunn , E. L. and Thompson , N. W.Anaplastic spindle‐cell and giant‐cell tumors of the thyroid gland . Cancer , 30 , 113 – 127 ( 1972. ). [DOI] [PubMed] [Google Scholar]
  • 5. ) Jao , W. and Gould , V. E.Ultrastructure of anaplastic (spindle and giant cell) carcinoma of the thyroid . Cancer , 35 , 1280 – 1292 ( 1975. ). [DOI] [PubMed] [Google Scholar]
  • 6. ) Harada , T. , Ito , K. , Shimaoka , K. , Hosoda , Y. and Yakumaru , K.Fatal thyroid carcinoma: anaplastic transformation of adenocarcinoma . Cancer , 39 , 2588 – 2596 ( 1977. ). [DOI] [PubMed] [Google Scholar]
  • 7. ) Rosai , J. and Carcangiu , M. L.Pathology of thyroid tumors: some recent and old questions . Hum. Pathol , 15 , 1008 – 1012 ( 1984. ). [DOI] [PubMed] [Google Scholar]
  • 8. ) Levine , A. J. , Momand , J. and Finlay , C. A.The p53 tumor suppressor gene . Nature , 351 , 453 – 456 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 9. ) Hollstein , M. , Sidransky , D. , Vogelstein , B. and Harris , C. C.p53 mutations in human cancers . Science , 253 , 49 – 53 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 10. ) Fearon , E. R. and Vogelstein , B.A genetic model for colorectal tumorigenesis . Cell , 61 , 759 – 767 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 11. ) Foti , A. , Ahuja , H. G. , Allen , S. L. , Koduru , P. , Schuster , M. W. , Schulman , P. , Bar‐Eli , M. and Cline , M. J.Correlation between molecular and clinical events in the evolution of chronic myelocytic leukemia to blast crisis . Blood , 77 , 2441 – 2444 ( 1991. ). [PubMed] [Google Scholar]
  • 12. ) Sidransky , D. , Mikkelsen , T. , Schwechheimer , K. , Rosenblum , M. L. , Cavanee , W. and Vogelstein , B.Clonal expansion of p53 mutant cells is associated with brain tumor progression . Nature , 355 , 846 – 847 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 13. ) Sato , T. , Tanigami , A. , Yamanaka , 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]
  • 14. ) Saiki , R. K. , Scharf , S. , Faloona , F. , Mullis , K. B. , Horn , G. T. , Erlich , H. A. and Arnheim , N.Enzymatic amplification of β‐globin genomic sequences and restriction site analysis for diagnosis of sickle cell anemia . Science , 230 , 1350 – 1354 ( 1985. ). [DOI] [PubMed] [Google Scholar]
  • 15. ) Saiki , R. K. , Gelfand , D. H. , Stoffel , S. , Scharf , S. J. , Higuchi , R. , Horn , G. T. , Mullis , K. B. and Erlich , H. A.Primer‐directed enzymatic amplification of DNA with a thermostable DNA polymerase . Science , 239 , 487 – 491 ( 1988. ). [DOI] [PubMed] [Google Scholar]
  • 16. ) Winter , E. , Yamamoto , F. , Almoguera , C. and Perucho , M.A method to detect and characterize point mutations in transcribed genes: amplification and overexpression of the mutant c‐Ki‐ras allele in human tumor cells . Proc. Natl. Acad. Sci. USA , 82 , 7575 – 7579 ( 1985. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17. ) Myers , R. M. , Larin , Z. and Maniatis , T.Detection of single base substitutions by ribonuclease cleavage at mismatches in RNA:DNA duplexes . Science , 230 , 1242 – 1246 ( 1985. ). [DOI] [PubMed] [Google Scholar]
  • 18. ) Kinzler , K. W. , Nilbert , M. C. , Vogelstein , B. , Bryan , T. M. , Levy , D. B. , Smith , K. J. , Preisinger , A. C. , Hamilton , S. R. , Hedge , P. , Markham , A. , Carlson , M. , Joslyn , G. , Groden , J. , White , R. , Miki , Y. , Miyoshi , Y. , Nishisho , I. and Nakamura , Y.Identification of a gene located at chromosome 5q21 that is mutated in colorectal cancers . Science , 251 , 1366 – 1370 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 19. ) Del Sal , G. , Manfioletti , G. and Schneider , C.The CTAB‐DNA precipitation method: a common mini‐scale preparation of template DNA from phagemids, phages or plasmids suitable for sequencing . BioTechniques , 7 , 514 – 521 ( 1989. ). [PubMed] [Google Scholar]
  • 20. ) Baker , S. J. , Fearon , E. R. , Nigro , J. M. , Hamilton , S. R. , Preisinger , A. C. , Jessup , J. M. , van Tuinen , P. , Ledbetter , D. H. , Barker , D. F. , Nakamura , Y. , White , R. and Vogelstein , B.Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas . Science , 244 , 217 – 221 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 21. ) Nigro , J. M. , Baker , S. J. , Preisinger , A. C. , Jessup , J. M. , Hostetter , R. , Cleary , K. , Bigner , S. H. , Davidson , N. , Baylin , S. , Devilee , P. , Glover , T. , Collins , F. S. , Weston , A. , Modali , R. , Harris , C. C. and Vogelstein , B.Mutations in the p53 gene occur in diverse human tumor types . Nature , 342 , 705 – 708 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 22. ) Takahashi , T. , Nau , M. M. , Chiba , I , Birrer , M. J. , Rosenberg , R. K. , Vinocour , M. , Levitt , M. , Pass , H. , Gazdar , A. F. and Minna , J. D.p53: a frequent target for genetic abnormalities in lung cancer . Science , 246 , 491 – 494 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 23. ) Chiba , I. , Takahashi , T. , Nau , M. M. , D'Amico , D. , Curiel , D. T. , Mitsudomi , T. , Buchhagen , D. L. , Carbone , D. , Piantadosi , S. , Koga , H. , Reissman , P. T. , Slamon , D. J. , Carmack Holmes , E. and Minna , J. D.Mutations in the p53 gene are frequent in primary, resected non‐small cell lung cancer . Oncogene , 5 , 1603 – 1610 ( 1990. ). [PubMed] [Google Scholar]
  • 24. ) D'Amico , D. , Carbone , D. , Mitsudomi , T. , Nau , M. , Fedorko , J. , Russell , E. , Johnson , B. , Buchhagen , D. , Bodner , S. , Phelps , R. , Gazdar , A. and Minna , J. D.High frequency of somatically acquired p53 mutations in small cell lung cancer cell lines and tumors . Oncogene , 7 , 339 – 346 ( 1992. ). [PubMed] [Google Scholar]
  • 25. ) Buchman , V. L. , Chumakov , P. M. , Ninkina , N. N. , Samarina , O. P. and Georgiev , G. P.A variation in the structure of the protein‐coding region of the human p53 gene . Gene , 70 , 245 – 252 ( 1988. ). [DOI] [PubMed] [Google Scholar]
  • 26. ) Soussi , T. , Caron de Fromentel , C. and May , P.Structural aspects of the p53 protein in relation to gene evolution . Oncogene , 5 , 945 – 952 ( 1990. ). [PubMed] [Google Scholar]
  • 27. ) Myers , R. M. and Maniatis , T.Recent advances in the development of methods for detecting single‐base substitutions associated with human genetic diseases . Cold Spring Harbor Symp. Quant. Biol , 51 , 275 – 284 ( 1986. ). [DOI] [PubMed] [Google Scholar]
  • 28. ) Suárez , H. G. , Du Villard , J. A. , Caillou , B. , Schlum‐berger , M. , Tubiana , M. , Parmentier , C. and Monier , R.Detection of activated ras oncogenes in human thyroid carcinomas . Oncogene , 2 , 403 – 406 ( 1988. ). [PubMed] [Google Scholar]
  • 29. ) Terrier , P. , Sheng , Z.‐M. , Schlumberger , M. , Tubiana , M. , Caillou , B. , Travagli , J.‐P. , Fragu , P. , Parmentier , C. and Riou , G.Structure and expression of c‐myc and c‐fos proto‐oncogenes in thyroid carcinomas . Br. J, Cancer , 57 , 43 – 47 ( 1988. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30. ) Aasland , R. , Lillehaug , J. R. , Male , R. , Jøsendal , O. , Varhaug , J. E. and Kleppe , K.Expression of oncogenes in thyroid tumours: coexpression of c‐erbB2/neu and c‐erbB . Br. J. Cancer , 57 , 358 – 363 ( 1988. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31. ) Miyoshi , J. , Higashi , T. , Mukai , H. , Ohuchi , T. and Kakunaga , T.Structure and transforming potential of the human cot oncogene encoding a putative protein kinase . Mol. Cell. Biol , 11 , 4088 – 4096 ( 1991. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32. ) Wright , P. A. , Lemoine , N. R. , Goretzki , P. E. , Wyllie , F. S. , Bond , J. , Hughes , C. , Roher , H.‐D. , Williams , E. D. and Wynford‐Thomas , D.Mutation of the p53 gene in a differentiated human thyroid carcinoma cell line, but not in primary thyroid tumours . Oncogene , 6 , 1693 – 1697 ( 1991. ). [PubMed] [Google Scholar]
  • 33. ) Ito , T. , Seyama , T. , Mizuno , T. , Tsuyama , N. , Hayashi , T. , Hayashi , Y. , Dohi , K. , Nakamura , N. and Akiyama , M.Unique association of p53 mutations with un‐differentiated but not with differentiated carcinomas of the thyroid gland . Cancer Res. , 52 , 1369 – 1371 ( 1992. ). [PubMed] [Google Scholar]

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