Journal of Clinical Endocrinology & Metabolism, Vol 81, 2881-2884, Copyright © 1996 by Endocrine Society

ARTICLES

Extensive mutation scanning of RET in sporadic medullary thyroid carcinoma and of RET and VHL in sporadic pheochromocytoma reveals involvement of these genes in only a minority of cases

RM Hofstra, T Stelwagen, RP Stulp, D de Jong, M Hulsbeek, EJ Kamsteeg, A van den Berg, RM Landsvater, A Vermey, WM Molenaar, CJ Lips and CH Buys
Department of Medical Genetics, University of Groningen, The Netherlands.

Sporadic medullary thyroid carcinoma (MTC) and pheochromocytoma (PC) have been reported to be associated with some specific RET gene mutations. To assess the role of RET in the development of MTC and PC, we screened 14 sporadic MTC, two MTC-derived cell lines, and 5 sporatic PC cases of RET mutations by a systematic analysis of the whole coding sequence, including all intron-exon junctions. In only 6 of the 14 sporadic MTC we were able to detect a RET mutation. Apart from the MET918-->Thr mutation in 5 of the MTC cases, we found a 3-bp deletion in exon 11, only present in the tumor, in another case. Analysis of 2 cell lines revealed the Met918-->Thr mutation in 1 and a Cys634-->Trp mutation in the other cell line. A possible somatic nature of these mutations could not be confirmed because in neither case was constitutive DNA available. We conclude that a large proportion of sporadic MTC must be due to mutations in an unidentified gene(s) other than RET. In none of the sporadic PC cases was a RET mutation found. As PC is a frequent complication in families suffering from von Hippel Lindau disease, for which mutations of the VHL gene are responsible, we also screened the 5 sporadic PC cases for VHL mutations. This revealed a Gly164-->Ser mutation in a single specimen. Thus, in PC, a large majority of tumors are due to mutations in an unidentified gene(s) other than RET and VHL.

This article has been cited by other articles:

				D. Cordella, M. Muzza, L. Alberti, P. Colombo, P. Travaglini, P. Beck-Peccoz, L. Fugazzola, and L. Persani An in-frame complex germline mutation in the juxtamembrane intracellular domain causing RET activation in familial medullary thyroid carcinoma. Endocr. Relat. Cancer, September 1, 2006; 13(3): 945 - 953. [Abstract] [Full Text] [PDF]

				C D E Margetts, D Astuti, D C Gentle, W N Cooper, A Cascon, D Catchpoole, M Robledo, H P H Neumann, F Latif, and E R Maher Epigenetic analysis of HIC1, CASP8, FLIP, TSP1, DCR1, DCR2, DR4, DR5, KvDMR1, H19 and preferential 11p15.5 maternal-allele loss in von Hippel-Lindau and sporadic phaeochromocytomas Endocr. Relat. Cancer, March 1, 2005; 12(1): 161 - 172. [Abstract] [Full Text] [PDF]

				W. Y. Kim and W. G. Kaelin Role of VHL Gene Mutation in Human Cancer J. Clin. Oncol., December 15, 2004; 22(24): 4991 - 5004. [Abstract] [Full Text] [PDF]

				G. Eisenhofer, S. R Bornstein, F. M Brouwers, N.-K. V Cheung, P. L Dahia, R. R de Krijger, T. J Giordano, L. A Greene, D. S Goldstein, H. Lehnert, et al. Malignant pheochromocytoma: current status and initiatives for future progress Endocr. Relat. Cancer, September 1, 2004; 11(3): 423 - 436. [Abstract] [Full Text] [PDF]

				E. R. Maher and C. Eng The pressure rises: update on the genetics of phaeochromocytoma Hum. Mol. Genet., October 1, 2002; 11(20): 2347 - 2354. [Abstract] [Full Text] [PDF]

				B E Baysal Hereditary paraganglioma targets diverse paraganglia J. Med. Genet., September 1, 2002; 39(9): 617 - 622. [Abstract] [Full Text] [PDF]

				C. A. Friedrich Genotype-phenotype correlation in von Hippel-Lindau syndrome Hum. Mol. Genet., April 1, 2001; 10(7): 763 - 767. [Abstract] [Full Text] [PDF]

				B. U. Bender, M. Gutsche, S. Gläsker, B. Müller, G. Kirste, C. Eng, and H. P. H. Neumann Differential Genetic Alterations in von Hippel-Lindau Syndrome-Associated and Sporadic Pheochromocytomas J. Clin. Endocrinol. Metab., December 1, 2000; 85(12): 4568 - 4574. [Abstract] [Full Text]

				O. Gimm, M. Armanios, H. Dziema, H. P. H. Neumann, and C. Eng Somatic and Occult Germ-line Mutations in SDHD, a Mitochondrial Complex II Gene, in Nonfamilial Pheochromocytoma Cancer Res., December 1, 2000; 60(24): 6822 - 6825. [Abstract] [Full Text]

				E. Edstrom, E. Mahlamaki, B. Nord, M. Kjellman, R. Karhu, A. Hoog, N. Goncharov, B. T. Teh, M. Backdahl, and C. Larsson Comparative Genomic Hybridization Reveals Frequent Losses of Chromosomes 1p and 3q in Pheochromocytomas and Abdominal Paragangliomas, Suggesting a Common Genetic Etiology Am. J. Pathol., February 1, 2000; 156(2): 651 - 659. [Abstract] [Full Text] [PDF]

				E.-M. Duerr, O. Gimm, D. S. Neuberg, J. B. Kum, S. C. Clifford, S. P. A. Toledo, E. R. Maher, P. L. M. Dahia, and C. Eng Differences in Allelic Distribution of Two Polymorphisms in the VHL-Associated Gene CUL2 in Pheochromocytoma Patients without Somatic CUL2 Mutations J. Clin. Endocrinol. Metab., September 1, 1999; 84(9): 3207 - 3211. [Abstract] [Full Text]

				D. J. Marsh, Z. Zheng, A. Arnold, S. D. Andrew, D. Learoyd, A. Frilling, P. Komminoth, H. P.H. Neumann, B. A.J. Ponder, B. J. Rollins, et al. Mutation Analysis of Glial Cell Line-Derived Neurotrophic Factor, a Ligand for an RET/Coreceptor Complex, in Multiple Endocrine Neoplasia Type 2 and Sporadic Neuroendocrine Tumors J. Clin. Endocrinol. Metab., September 1, 1997; 82(9): 3025 - 3028. [Abstract] [Full Text] [PDF]