Skip to main content
PMC home page
The American Journal of Pathology logoLink to The American Journal of Pathology
. 1995 Dec;147(6):1600–1607.

Absence of RET proto-oncogene point mutations in sporadic hyperplastic and neoplastic lesions of the parathyroid gland.

B C Padberg 1, S Schröder 1, W Jochum 1, H Kastendieck 1, J Roth 1, P U Heitz 1, P Komminoth 1
PMCID: PMC1869948  PMID: 7495285

Abstract

We investigated the possible role of RET proto-oncogene mutations in the development of sporadic hyperplastic, benign, and malignant parathyroid lesions. DNA extracted from paraffin-embedded specimens of forty parathyroid lesions was screened for RET proto-oncogene point mutations in exons 10, 11, and 16 by nonisotopic polymerase chain reaction-based single-strand conformation polymorphism and heteroduplex gel electrophoresis. The nucleotide sequence of samples with aberrant band patterns was identified by nonisotopic direct sequencing of polymerase chain reaction-amplified DNA. Parathyroids of seven patients with multiple endocrine neoplasia type 2A (MEN 2A) and MEN 2B served as positive controls. None of the eight hyperplastic lesions, three cases of parathyromatosis, ten parathyroid adenomas, eleven carcinomas or one normal parathyroid gland contained mutations in each of the three RET exons tested. Six MEN-2A-associated hyperplastic glands exhibited identical band shifts in the polymerase chain reaction single-strand conformation polymorphism analysis of exon 11, which corresponded to a Cys 634-->Arg substitution in the nucleotide sequence analysis (TGC-->CGC), whereas in the MEN 2B parathyroid specimen a point mutation was found at codon 918 of exon 16 (ATG-->ACG), causing a Met 918-->Thr substitution. Our data indicate that RET mutations of the MEN 2 loci in exons 10, 11, and 16 are not involved in the development of sporadically occurring benign or malignant parathyroid lesions. Furthermore, our results are in accordance with the observation that MEN 2A patients with Cys 634-->Arg (germline) mutations have a higher risk of developing parathyroid disease than those with other mutations at codon 634.

Full text

PDF

Images in this article

1603Figure 1
on p.1603
1603Figure 2
on p.1603

Selected References

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

  1. Arnold A., Kim H. G., Gaz R. D., Eddy R. L., Fukushima Y., Byers M. G., Shows T. B., Kronenberg H. M. Molecular cloning and chromosomal mapping of DNA rearranged with the parathyroid hormone gene in a parathyroid adenoma. J Clin Invest. 1989 Jun;83(6):2034–2040. doi: 10.1172/JCI114114. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Arnold A., Motokura T., Bloom T., Rosenberg C., Bale A., Kronenberg H., Ruderman J., Brown M., Kim H. G. PRAD1 (cyclin D1): a parathyroid neoplasia gene on 11q13. Henry Ford Hosp Med J. 1992;40(3-4):177–180. [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. Byström C., Larsson C., Blomberg C., Sandelin K., Falkmer U., Skogseid B., Oberg K., Werner S., Nordenskjöld M. Localization of the MEN1 gene to a small region within chromosome 11q13 by deletion mapping in tumors. Proc Natl Acad Sci U S A. 1990 Mar;87(5):1968–1972. doi: 10.1073/pnas.87.5.1968. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Chi D. D., Toshima K., Donis-Keller H., Wells S. A., Jr Predictive testing for multiple endocrine neoplasia type 2A (MEN 2A) based on the detection of mutations in the RET protooncogene. Surgery. 1994 Aug;116(2):124–133. [PubMed] [Google Scholar]
  6. Cryns V. L., Rubio M. P., Thor A. D., Louis D. N., Arnold A. p53 abnormalities in human parathyroid carcinoma. J Clin Endocrinol Metab. 1994 Jun;78(6):1320–1324. doi: 10.1210/jcem.78.6.8200932. [DOI] [PubMed] [Google Scholar]
  7. Cryns V. L., Thor A., Xu H. J., Hu S. X., Wierman M. E., Vickery A. L., Jr, Benedict W. F., Arnold A. Loss of the retinoblastoma tumor-suppressor gene in parathyroid carcinoma. N Engl J Med. 1994 Mar 17;330(11):757–761. doi: 10.1056/NEJM199403173301105. [DOI] [PubMed] [Google Scholar]
  8. Donis-Keller H., Dou S., Chi D., Carlson K. M., Toshima K., Lairmore T. C., Howe J. R., Moley J. F., Goodfellow P., Wells S. A., Jr Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Hum Mol Genet. 1993 Jul;2(7):851–856. doi: 10.1093/hmg/2.7.851. [DOI] [PubMed] [Google Scholar]
  9. Eng C., Mulligan L. M., Smith D. P., Healey C. S., Frilling A., Raue F., Neumann H. P., Pfragner R., Behmel A., Lorenzo M. J. Mutation of the RET protooncogene in sporadic medullary thyroid carcinoma. Genes Chromosomes Cancer. 1995 Mar;12(3):209–212. doi: 10.1002/gcc.2870120308. [DOI] [PubMed] [Google Scholar]
  10. Eng C., Smith D. P., Mulligan L. M., Healey C. S., Zvelebil M. J., Stonehouse T. J., Ponder M. A., Jackson C. E., Waterfield M. D., Ponder B. A. A novel point mutation in the tyrosine kinase domain of the RET proto-oncogene in sporadic medullary thyroid carcinoma and in a family with FMTC. Oncogene. 1995 Feb 2;10(3):509–513. [PubMed] [Google Scholar]
  11. Eng C., Smith D. P., Mulligan L. M., Nagai M. A., Healey C. S., Ponder M. A., Gardner E., Scheumann G. F., Jackson C. E., Tunnacliffe A. Point mutation within the tyrosine kinase domain of the RET proto-oncogene in multiple endocrine neoplasia type 2B and related sporadic tumours. Hum Mol Genet. 1994 Feb;3(2):237–241. doi: 10.1093/hmg/3.2.237. [DOI] [PubMed] [Google Scholar]
  12. Eng C., Smith D. P., Mulligan L. M., Nagai M. A., Healey C. S., Ponder M. A., Gardner E., Scheumann G. F., Jackson C. E., Tunnacliffe A. Point mutation within the tyrosine kinase domain of the RET proto-oncogene in multiple endocrine neoplasia type 2B and related sporadic tumours. Hum Mol Genet. 1994 Feb;3(2):237–241. doi: 10.1093/hmg/3.2.237. [DOI] [PubMed] [Google Scholar]
  13. Fitko R., Roth S. I., Hines J. R., Roxe D. M., Cahill E. Parathyromatosis in hyperparathyroidism. Hum Pathol. 1990 Feb;21(2):234–237. doi: 10.1016/0046-8177(90)90136-s. [DOI] [PubMed] [Google Scholar]
  14. Friedman E., Bale A. E., Marx S. J., Norton J. A., Arnold A., Tu T., Aurbach G. D., Spiegel A. M. Genetic abnormalities in sporadic parathyroid adenomas. J Clin Endocrinol Metab. 1990 Aug;71(2):293–297. doi: 10.1210/jcem-71-2-293. [DOI] [PubMed] [Google Scholar]
  15. Friedman E., De Marco L., Gejman P. V., Norton J. A., Bale A. E., Aurbach G. D., Spiegel A. M., Marx S. J. Allelic loss from chromosome 11 in parathyroid tumors. Cancer Res. 1992 Dec 15;52(24):6804–6809. [PubMed] [Google Scholar]
  16. Friedman E., Sakaguchi K., Bale A. E., Falchetti A., Streeten E., Zimering M. B., Weinstein L. S., McBride W. O., Nakamura Y., Brandi M. L. Clonality of parathyroid tumors in familial multiple endocrine neoplasia type 1. N Engl J Med. 1989 Jul 27;321(4):213–218. doi: 10.1056/NEJM198907273210402. [DOI] [PubMed] [Google Scholar]
  17. Gramlich T. L., Fritsch C. R., Maurer D., Eberle M., Gansler T. S. Differential polymerase chain reaction assay of cyclin D1 gene amplification in esophageal carcinoma. Diagn Mol Pathol. 1994 Dec;3(4):255–259. doi: 10.1097/00019606-199412000-00007. [DOI] [PubMed] [Google Scholar]
  18. 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]
  19. Hakim J. P., Levine M. A. Absence of p53 point mutations in parathyroid adenoma and carcinoma. J Clin Endocrinol Metab. 1994 Jan;78(1):103–106. doi: 10.1210/jcem.78.1.8288693. [DOI] [PubMed] [Google Scholar]
  20. Halloran N., Du Z., Wilson R. K. Sequencing reactions for the applied biosystems 373A Automated DNA Sequencer. Methods Mol Biol. 1993;23:297–315. doi: 10.1385/0-89603-248-5:297. [DOI] [PubMed] [Google Scholar]
  21. Hofstra R. M., Landsvater R. M., Ceccherini I., Stulp R. P., Stelwagen T., Luo Y., Pasini B., Höppener J. W., van Amstel H. K., Romeo G. A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature. 1994 Jan 27;367(6461):375–376. doi: 10.1038/367375a0. [DOI] [PubMed] [Google Scholar]
  22. Kollmorgen C. F., Aust M. R., Ferreiro J. A., McCarthy J. T., van Heerden J. A. Parathyromatosis: a rare yet important cause of persistent or recurrent hyperparathyroidism. Surgery. 1994 Jul;116(1):111–115. [PubMed] [Google Scholar]
  23. Komminoth P., Kunz E. K., Matias-Guiu X., Hiort O., Christiansen G., Colomer A., Roth J., Heitz P. U. Analysis of RET protooncogene point mutations distinguishes heritable from nonheritable medullary thyroid carcinomas. Cancer. 1995 Aug 1;76(3):479–489. doi: 10.1002/1097-0142(19950801)76:3<479::aid-cncr2820760319>3.0.co;2-m. [DOI] [PubMed] [Google Scholar]
  24. Komminoth P., Kunz E., Hiort O., Schröder S., Matias-Guiu X., Christiansen G., Roth J., Heitz P. U. Detection of RET proto-oncogene point mutations in paraffin-embedded pheochromocytoma specimens by nonradioactive single-strand conformation polymorphism analysis and direct sequencing. Am J Pathol. 1994 Oct;145(4):922–929. [PMC free article] [PubMed] [Google Scholar]
  25. Kurzrock R., Ku S., Talpaz M. Abnormalities in the PRAD1 (CYCLIN D1/BCL-1) oncogene are frequent in cervical and vulvar squamous cell carcinoma cell lines. Cancer. 1995 Jan 15;75(2):584–590. doi: 10.1002/1097-0142(19950115)75:2<584::aid-cncr2820750223>3.0.co;2-p. [DOI] [PubMed] [Google Scholar]
  26. Larsson C., Skogseid B., Oberg K., Nakamura Y., Nordenskjöld M. Multiple endocrine neoplasia type 1 gene maps to chromosome 11 and is lost in insulinoma. Nature. 1988 Mar 3;332(6159):85–87. doi: 10.1038/332085a0. [DOI] [PubMed] [Google Scholar]
  27. Lips C. J., Landsvater R. M., Höppener J. W., Geerdink R. A., Blijham G., van Veen J. M., van Gils A. P., de Wit M. J., Zewald R. A., Berends M. J. Clinical screening as compared with DNA analysis in families with multiple endocrine neoplasia type 2A. N Engl J Med. 1994 Sep 29;331(13):828–835. doi: 10.1056/NEJM199409293311302. [DOI] [PubMed] [Google Scholar]
  28. Motokura T., Arnold A. Cyclin D and oncogenesis. Curr Opin Genet Dev. 1993 Feb;3(1):5–10. doi: 10.1016/s0959-437x(05)80334-x. [DOI] [PubMed] [Google Scholar]
  29. Motokura T., Arnold A. PRAD1/cyclin D1 proto-oncogene: genomic organization, 5' DNA sequence, and sequence of a tumor-specific rearrangement breakpoint. Genes Chromosomes Cancer. 1993 Jun;7(2):89–95. doi: 10.1002/gcc.2870070205. [DOI] [PubMed] [Google Scholar]
  30. Mulligan L. M., Eng C., Healey C. S., Clayton D., Kwok J. B., Gardner E., Ponder M. A., Frilling A., Jackson C. E., Lehnert H. Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN 2A and FMTC. Nat Genet. 1994 Jan;6(1):70–74. doi: 10.1038/ng0194-70. [DOI] [PubMed] [Google Scholar]
  31. Mulligan L. M., Kwok J. B., Healey C. S., Elsdon M. J., Eng C., Gardner E., Love D. R., Mole S. E., Moore J. K., Papi L. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature. 1993 Jun 3;363(6428):458–460. doi: 10.1038/363458a0. [DOI] [PubMed] [Google Scholar]
  32. Pachnis V., Mankoo B., Costantini F. Expression of the c-ret proto-oncogene during mouse embryogenesis. Development. 1993 Dec;119(4):1005–1017. doi: 10.1242/dev.119.4.1005. [DOI] [PubMed] [Google Scholar]
  33. Quadro L., Panariello L., Salvatore D., Carlomagno F., Del Prete M., Nunziata V., Colantuoni V., Di Giovanni G., Brandi M. L., Mannelli M. Frequent RET protooncogene mutations in multiple endocrine neoplasia type 2A. J Clin Endocrinol Metab. 1994 Aug;79(2):590–594. doi: 10.1210/jcem.79.2.7913936. [DOI] [PubMed] [Google Scholar]
  34. Rosenberg C. L., Motokura T., Kronenberg H. M., Arnold A. Coding sequence of the overexpressed transcript of the putative oncogene PRAD1/cyclin D1 in two primary human tumors. Oncogene. 1993 Feb;8(2):519–521. [PubMed] [Google Scholar]
  35. Schuffenecker I., Billaud M., Calender A., Chambe B., Ginet N., Calmettes C., Modigliani E., Lenoir G. M. RET proto-oncogene mutations in French MEN 2A and FMTC families. Hum Mol Genet. 1994 Nov;3(11):1939–1943. doi: 10.1093/hmg/3.11.1939. [DOI] [PubMed] [Google Scholar]
  36. Seto M., Yamamoto K., Iida S., Akao Y., Utsumi K. R., Kubonishi I., Miyoshi I., Ohtsuki T., Yawata Y., Namba M. Gene rearrangement and overexpression of PRAD1 in lymphoid malignancy with t(11;14)(q13;q32) translocation. Oncogene. 1992 Jul;7(7):1401–1406. [PubMed] [Google Scholar]
  37. 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]
  38. 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]
  39. Tautz D., Renz M. An optimized freeze-squeeze method for the recovery of DNA fragments from agarose gels. Anal Biochem. 1983 Jul 1;132(1):14–19. doi: 10.1016/0003-2697(83)90419-0. [DOI] [PubMed] [Google Scholar]
  40. Thakker R. V., Bouloux P., Wooding C., Chotai K., Broad P. M., Spurr N. K., Besser G. M., O'Riordan J. L. Association of parathyroid tumors in multiple endocrine neoplasia type 1 with loss of alleles on chromosome 11. N Engl J Med. 1989 Jul 27;321(4):218–224. doi: 10.1056/NEJM198907273210403. [DOI] [PubMed] [Google Scholar]
  41. Vessey S. J., Jones P. M., Wallis S. C., Schofield J., Bloom S. R. Absence of mutations in the Gs alpha and Gi2 alpha genes in sporadic parathyroid adenomas and insulinomas. Clin Sci (Lond) 1994 Nov;87(5):493–497. doi: 10.1042/cs0870493. [DOI] [PubMed] [Google Scholar]
  42. Wells S. A., Jr, Chi D. D., Toshima K., Dehner L. P., Coffin C. M., Dowton S. B., Ivanovich J. L., DeBenedetti M. K., Dilley W. G., Moley J. F. Predictive DNA testing and prophylactic thyroidectomy in patients at risk for multiple endocrine neoplasia type 2A. Ann Surg. 1994 Sep;220(3):237–250. doi: 10.1097/00000658-199409000-00002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Yoshimoto K., Iwahana H., Fukuda A., Sano T., Itakura M. Rare mutations of the Gs alpha subunit gene in human endocrine tumors. Mutation detection by polymerase chain reaction-primer-introduced restriction analysis. Cancer. 1993 Aug 15;72(4):1386–1393. doi: 10.1002/1097-0142(19930815)72:4<1386::aid-cncr2820720439>3.0.co;2-j. [DOI] [PubMed] [Google Scholar]
  44. Yoshimoto K., Iwahana H., Fukuda A., Sano T., Katsuragi K., Kinoshita M., Saito S., Itakura M. ras mutations in endocrine tumors: mutation detection by polymerase chain reaction-single strand conformation polymorphism. Jpn J Cancer Res. 1992 Oct;83(10):1057–1062. doi: 10.1111/j.1349-7006.1992.tb02722.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Yoshimoto K., Iwahana H., Fukuda A., Sano T., Saito S., Itakura M. Role of p53 mutations in endocrine tumorigenesis: mutation detection by polymerase chain reaction-single strand conformation polymorphism. Cancer Res. 1992 Sep 15;52(18):5061–5064. [PubMed] [Google Scholar]

Articles from The American Journal of Pathology are provided here courtesy of American Society for Investigative Pathology

RESOURCES