Abstract
To elucidate the molecular basis for endocrine tumorigenesis, ras mutations in human endocrine tumors were analyzed using polymerase chain reaction‐single strand conformation polymorphism (PCR‐SSCP) analysis. Mutations of the H‐, K‐, N‐ras genes were examined in genomic DNAs from 169 successfully amplified primary endocrine tumors out of 189 samples. Four out of 24 thyroid follicular adenomas analyzed contained mutated N‐ras codon 61, and one contained the mutated H‐ras codon 61. One of the 19 pheochromocytomas revealed mutation of the H‐ras codon 13. No mutations of the ras gene were detected in pituitary adenomas, parathyroid tumors, thyroid cancers, endocrine pancreatic tumors, and adrenocortical tumors. Based on these findings we conclude that activation of the ras gene may play a role in the tumorigenesis of a limited number of thyroid follicular adenomas and pheochromocytomas, and that mutation of the ras gene is not frequent in other human endocrine tumors.
Keywords: ras Gene, Missense mutation, Thyroid follicular adenoma, Pheochromocytoma
Full Text
The Full Text of this article is available as a PDF (385.7 KB).
REFERENCES
- 1. ) Lemoine , N. R. , May all , E. S. , Wyllie , F. S. , Farr , C. J. , Hughes , D. , Padua , R. A. , Thurston , V. , Williams , E. D. and Wynford‐Thomas , D.Activated ras oncogenes in human thyroid cancers . Cancer Res. , 48 , 4459 – 4463 ( 1988. ). [PubMed] [Google Scholar]
- 2. ) 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]
- 3. ) Wright , P. A , Lemoine , N. R. , Mayall , E. S. , Wyllie , F. S. , Hughes , D. , Williams , E. D. and Wynford‐Thomas , D.Papillary and follicular thyroid carcinomas show a different pattern of ras oncogene mutation . Br. J. Cancer , 60 , 576 – 577 ( 1989. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. ) Namba , H. , Rubin , S. A. and Fagin , J. A.Point mutations of ras oncogenes are an early event in thyroid tumorigenesis . Mot Endocrinol , 4 , 1474 – 1479 ( 1990. ). [DOI] [PubMed] [Google Scholar]
- 5. ) Suarez , H. G. , Villard , J. A. D. , 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]
- 6. ) Wright , P. A. , Williams , E. D. , Lemoine , N. R. and Wynford‐Thomas , D.Radiation‐associated and ‘spontaneous’ human thyroid carcinomas show a different pattern of ras oncogene mutation . Oncogene , 6 , 471 – 473 ( 1991. ). [PubMed] [Google Scholar]
- 7. ) Karga , H. , Lee , J‐K. , Vickery , A. L. , 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]
- 8. ) 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 iodine‐deficient area . Cancer Res. , 51 , 2690 – 2693 ( 1991. ). [PubMed] [Google Scholar]
- 9. ) Karga , H. J. , Alexander , J. M. , Hedley‐Whyte , E. T. , Klibanski , A. and Jameson , J. L.Ras mutations in human pituitary tumors . J. Clin. Endocrinol. Metab. , 74 , 914 – 919 ( 1992. ). [DOI] [PubMed] [Google Scholar]
- 10. ) Grieco , M. , Santro , M. , Berlingieri , M. T. , Melillo , R. M. , Donghi , R. , Pierotti , M. A. and Porta , G. D.PTC is a novel rearranged form of the ret proto‐oncogene and frequently detected in vivo in human papillary thyroid carcinomas . Cell , 60 , 557 – 563 ( 1990. ). [DOI] [PubMed] [Google Scholar]
- 11. ) Ishizaka , Y. , Kobayashi , S. , Ushijima , T. , Hirohashi , S. , Sugimura , T. and Nagao , M.Detection of retTPC/PTC transcripts in thyroid adenomas and adenomatous goiter by an RT‐PCR method . Oncogene , 6 , 1667 – 1672 ( 1991. ). [PubMed] [Google Scholar]
- 12. ) Lyons , J. , Landis , C. A. , Harsh , G. , Vallar , L. , Grunewald , K. , Feichtinger , H. , Ouan‐Yang , D. and Clark , O. H.Two G protein oncogenes in human endocrine tumors . Science , 249 , 655 – 659 ( 1990. ). [DOI] [PubMed] [Google Scholar]
- 13. ) Wright , P. A. , Lemoine , N. R. , Goretzki , 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 tumors . Oncogene , 6 , 1693 – 1697 ( 1991. ). [PubMed] [Google Scholar]
- 14. ) Ito , T. , Seyama , T. , Mizuno , T. , Tsuyama , N. , Hayashi , Y. , Dohi , K. , Nakamura , N. and Akiyama , M.Unique association of p53 mutations with undifferentiated but not with differentiated carcinomas of the thyroid gland . Cancer Res. , 52 , 1369 – 1371 ( 1992. ). [PubMed] [Google Scholar]
- 15. ) Bos , J. L.ras oncogenes in human cancer: a review . Cancer Res. , 49 , 4682 – 4689 ( 1989. ). [PubMed] [Google Scholar]
- 16. ) Orita , M. , Suzuki , Y. , Sekiya , T. and Hayashi , K.Rapid and sensitive detection of point mutations and DNA polymorphism using the polymerase chain reaction . Genomics , 5 , 874 – 879 ( 1989. ). [DOI] [PubMed] [Google Scholar]
- 17. ) Yoshimoto , K. , Iizuka , M. , Iwahana , H. , Yamasaki , R. , Saito , H. , Saito , S. and Sekiya , T.Loss of the same alleles of HRAS1 and D11S151 in two independent pancreatic cancers from a patient with multiple endocrine neoplasia type 1 . Cancer Res. , 49 , 2716 – 2721 ( 1989. ). [PubMed] [Google Scholar]
- 18. ) Suzuki , Y. , Orita , M. , Shiraishi , M. , Hayashi , K. and Sekiya , T.Detection of ras gene mutations in human lung cancers by single‐strand conformation polymorphism analysis of polymerase chain reaction products . Oncogene , 5 , 1037 – 1043 ( 1990. ). [PubMed] [Google Scholar]
- 19. ) Saiki , R. K. , Scharf , S. , Faloona , F. , Mullis , K. B. , Horn , G. T. , Erlich , H. A. and Arnheim , M.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]
- 20. ) Suzuki , Y. , Sekiya , T. and Hayashi , K.Allele‐specific PCR: a method for amplification and sequence determination of a single component among a mixture of sequence variants . Anal. Biochem. , 192 , 82 – 84 ( 1991. ). [DOI] [PubMed] [Google Scholar]
- 21. ) Brown , R. , Marshall , C. J. , Pennie , G. S. and Hall , A.Mechanism of activation of an N‐ras gene in the human fibrosarcoma cell line HT1080 . EMBO J. , 3 , 1321 – 1326 ( 1984. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. ) Barbacid , M.ras genes . Ann. Rev. Biochem. , 56 , 779 – 827 ( 1987. ). [DOI] [PubMed] [Google Scholar]
- 23. ) Noda , M. , Ko , M. , Ogura , A. , Liu , D. , Amano , T. , Takano , T. and Ikawa , Y.Sarcoma viruses carrying ras oncogenes induce differentiation‐associated properties in a neuronal cell line . Nature , 318 , 73 – 75 ( 1985. ). [DOI] [PubMed] [Google Scholar]
- 24. ) Nakagawa , T. , Mabry , M. , Bustros , A. , Ihle , J. N. , Nelkin , B. D. and Baylin , S. B.Introduction of v‐Ha‐ras oncogene induces differentiation of cultured human medullary carcinoma cells . Proc. Natl Acad. Sci. USA , 84 , 5923 – 5927 ( 1987. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25. ) Hagag , N. , Halegoua , S. and Viola , M.Inhibition of growth factor‐induced differentiation of PC 12 cells by microinjection of antibody to ras p21 . Nature , 319 , 680 – 682 ( 1986. ). [DOI] [PubMed] [Google Scholar]
- 26. ) 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]
- 27. ) Visvanathan , K. , Pocock , R. D. and Summerhayers , I. C.Preferential and novel activation of H‐ras in human bladder carcinomas . Oncogene Res. , 3 , 77 – 86 ( 1988. ). [PubMed] [Google Scholar]
- 28. ) Nagata , Y. , Abe , M. , Kobayashi , K. , Saiki , S. , Kotake , T. , Yoshikawa , K. , Ueda , R. , Nakayama , E. and Shiku , H.Point mutations of c‐ras genes in human bladder cancer and kidney cancer . Jpn. J. Cancer Res. , 81 , 22 – 27 ( 1990. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29. ) Tadokoro , K. , Ueda , M. , Ohshima , T. , Fujita , K. , Rikimaru , K. , Takahashi , N. , Enomoto , S. and Tsuchida , N.Activation of oncogenes in human oral cancer cells: a novel codon 13 mutation of c‐H‐ras‐1 and concurrent amplifications of c‐erbB‐1 and c‐myc . Oncogene , 4 , 499 – 505 ( 1989. ). [PubMed] [Google Scholar]
- 30. ) Eliyahu , D. , Raz , A. , Gruss , P. , Givol , D. and Oren , M.Participation of p53 cellular tumour antigen in transformation of normal embryonic cells . Nature , 312 , 646 – 659 ( 1984. ). [DOI] [PubMed] [Google Scholar]
- 31. ) Lehman , T. A. , Bennet , W. P. , Metcalf , R. A. , Welsh , J. A. , Modali , R. V. , Ulrich , S. , Romano , J. W. , Appella , E. , Testa , J. R. , Gerwin , B. I. and Harris , C. C.p53 mutations, ras mutations, and p53‐heat shock 70 protein complexes in human lung carcinoma cell lines . Cancer Res. , 51 , 4090 – 4096 ( 1991. ). [PubMed] [Google Scholar]
- 32. ) Shaw , P. , Tardy , S. , Benito , E. , Obrador , A. and Costa , J.Occurrence of Ki‐ras and p53 mutations in primary colorectal tumors . Oncogene , 6 , 2121 – 2128 ( 1991. ). [PubMed] [Google Scholar]
- 33. ) Hollstein , M. C. , Peri , L. , Mandard , A. M. , Welsh , J. A. , Montesano , R.Metcalf , R. A. , Bak , M. and Harris , C. C.Genetic analysis of human esophageal tumors from two high incidence geographic areas: frequent p53 base substitutions and absence of ras mutations . Cancer Res. , 51 , 4102 – 4106 ( 1991. ). [PubMed] [Google Scholar]