Abstract
We investigated mutations of the ret proto‐oncogene in Japanese patients with multiple endocrine neoplasia (MEN) type 2A and type 2B. DNAs from pheochromocytomas and/or medullary thyroid carcinomas (MTCs) of five MEN 2A and three MEN 2B patients were amplified by a polymerase chain reaction (PCR) and analyzed. Tumors of four MEN 2A patients had missense mutations in Cys 634 in the extracellular domain of the ret proto‐oncogene. The same mutations were detected in normal tissues of the patients, indicating that the mutations had arisen in the germ line. Using a reverse transcriptase(RT)‐PCR, both normal and mutant transcripts of the ret proto‐oncogene were detected in a tumor of one patient with MEN 2A mutation. In addition, three MEN 2B patients examined had the same point mutation (ATGÂG) at codon 918 in the tyrosine kinase domain of the ret proto‐oncogene. Since all mutations identified in this study generated new restriction enzyme sites or eliminated a restriction site, the mutant alleles of affected family members could be readily detected without sequencing.
Keywords: MEN 2A, MEN 2B, ret proto‐oncogene, Germ line mutation
Full Text
The Full Text of this article is available as a PDF (260.9 KB).
REFERENCES
- 1. ) Gardner , E. , Papi , L.Easton , D. F. , Cummings , T. , Jackson , C. E. , Kaplan , M. , Love , D. R. , Mole , S. E. , Moore , J. K. , Mulligan , L. M. , Norum , R. A. , Ponder , M. A. , Reichlin , S. , Stall , G. , Telenius , H. , Telenius‐Berg , M. , Tunnacliffe , A. and Ponder , B. A. J.Genetic linkage studies map the multiple endocrine neoplasia type 2 loci to a small interval on chromosome 10q11.2 . Hum, Mol. Genet. , 2 , 241 – 246 ( 1993. ). [DOI] [PubMed] [Google Scholar]
- 2. ) Mole , S. E. , Mulligan , L. M. , Healey , C. S. , Ponder , B. A. J. and Tunnacliffe , A.Localisation of the gene for multiple endocrine neoplasia type 2A to a 480 kb region in chromosome band 10q11.2 . Hum. Mol Genet. , 2 , 247 – 252 ( 1993. ). [DOI] [PubMed] [Google Scholar]
- 3. ) Mulligan , L. M. , Kwok , J. B. J. , Healey , C. S. , Elsdon , M. J. , Eng , C. , Gardner , E. , Love , D. R. , Mole , S. E. , Moore , J. K. , Papi , L. , Ponder , M. A. , Telenius , H. , Tunnacliffe , A and Ponder , B. A. J.Germ‐line mutations of the RET proto‐oncogene in multiple endocrine neoplasia type 2A . Nature , 363 , 458 – 460 ( 1993. ). [DOI] [PubMed] [Google Scholar]
- 4. ) Donis‐Keller , H. , Dou , S. , Chi , D. , Carlson , K. M. , Toshima , K. , Lairmore , T. C. , Howe , J. R. , Moley , J. F. , Goodfellow , P. and Wells , S. A.Mutations in the RET proto‐oncogene are associated with MEN 2A and FMTC . Hum, Mol. Genet. , 2 , 851 – 856 ( 1993. ). [DOI] [PubMed] [Google Scholar]
- 5. ) 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]
- 6. ) Hofstra , R. M. W. , Landsvater , R. M. , Ceccherini , I. , Stulp , R. P. , Stelwagen , T. , Luo , Y. , Pasini , B. , Hoppener , J. W. M. , van Amstel , H. K. P. , Romeo , G. , Lips , C. J. M. and Buys , C. H. C. M.A mutation in the RET proto‐oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma . Nature , 367 , 375 – 376 ( 1994. ). [DOI] [PubMed] [Google Scholar]
- 7. ) Carlson , K. M. , Dou , S. , Chi , D. , Scavarda , N. , Toshima , K. , Jackson , C. E. , Wells , S. A. , Goodfellow , P. J. and Donis‐Keller , H.Single missense mutation in the tyrosine kinase catalytic domain of the RET protooncogene is associated with multiple endocrine neoplasia type 2B , Proc. Natl. Acad. Sci. USA , 91 , 1579 – 1583 ( 1994. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. ) Ceccherini , I. , Bocciardi , R. , Luo , Y. , Pasini , B. , Hofstra , R. , Takahashi , M. and Romeo , G.Exon structure and flanking intronic sequences of the human RET proto‐oncogene . Biochem. Biophys. Res. Commun. , 196 , 1288 – 1295 ( 1993. ). [DOI] [PubMed] [Google Scholar]
- 9. ) Takahashi , M. , Buma , Y. , Iwamoto , T. , Inaguma , Y. , Ikeda , H. and Hiai , H.Cloning and expression of the ret proto‐oncogene encoding a tyrosine kinase with two potential transmembrane domains . Oncogens , 3 , 571 – 578 ( 1988. ). [PubMed] [Google Scholar]
- 10. ) Yoshimoto , K. , Iwahara , H. and Itakura , M.Relatively good prognosis of multiple endocrine neoplasia type 2B in Japanese: review of cases in Japan and analysis of genetic changes in tumors . Endocr. J. , 40 , 649 – 657 ( 1993. ). [DOI] [PubMed] [Google Scholar]
- 11. ) Schuchardt , A. , D'Agati , V. , Larsson‐Blomberg , L. , Constantini , F. and Pachnis , V.Defect in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret . Nature , 367 , 380 – 383 ( 1994. ). [DOI] [PubMed] [Google Scholar]
- 12. ) Takahashi , M. , Buma , Y. and Hiai , H.Isolation of ret proto‐oncogene cDNA with an ammo‐terminal signal sequence . Oncogene , 4 , 805 – 806 ( 1989. ). [PubMed] [Google Scholar]