Mutations in the Cysteine-Rich Region of the RET Proto-Oncogene in Patients Diagnosed as Having Sporadic Medullary Thyroid Carcinoma.

Abstract

In this region, no mutations were detected in any tumors from patients with MEN 2B and NF1, and sporadic pheochromocytomas.But mutations were detected and identified in 3 clinically apparent sporadic MTCs and TT cells. A 6 base pair (bp) deletion causing the loss of a cysteine residue at codon 634 and a mutation causing substitution from cysteine to tyrosine at codon 634 were detected in 2 sporadic MTCs as somatic events. In a female patient diagnosed as having sporadic MTC, a mutation at codon 618 was detected not only in tumor tissues, but also in her leukocytes, suggesting a germline mutation of the RET proto-oncogene. In TT cells a heterozygous mutation at codon 634 was detected.These results suggest that RET mutations within a cysteine-rich region may also play an important role in the tumorigenesis of sporadic MTCs, and mutations of RET proto-oncogene should be screened in clinically sporadic cases to exclude hereditary MTCs.

Absence of Mutations at Codon 768 of the RET Proto-Oncogene in Sporadic and Hereditary Pheochromocytomas.

“…We also found no mutations in the cysteine-rich region in 12 sporadic pheochromocytomas and 3 pheochromocytomas with NF1 [16]. Recently, we found codon 918 mutations in 31% of sporadic pheochromocytomas (cases 13-16 in Table 1 in this study), for which mutations were heterozygous and tumor-specific [9].…”

“…By analogy applied to other inherited cancer syndromes, somatic mutations corresponding to germline mutations were observed in MEN 2A, FMTC and MEN 2B. In sporadic MTC, 23-40% had codon 918 mutations [3,14,15], but mutations in the cysteine-rich region were rare [4,16]. Recently, a missense mutation at codon 768 in the tyrosine kinase domain of the RET proto-oncogene was also detected in 40% of sporadic MTCs which do not have codon 918 mutations [8].…”

A complex nine base pair deletion in RET exon 11 common in sporadic medullary thyroid carcinoma

“…The most commonly seen mutations alter codons 918, 883 or 768, each in a small proportion of cases (Donis-Keller, 1995;Lloyd, 1995). However, two reports have mentioned the deletion of 6 bp including codon 630 or 634, each in a single case of sporadic MTC (Donis-Keller, 1995;Kimura et al, 1995).…”

“…In addition, the deletion of six bases removing a cysteine at codon 630 or 634 has been reported in two separate cases of sporadic MTC. (S Dou and H Donis-Keller, personal communication; Kimura et al, 1995).…”

An in-frame complex germline mutation in the juxtamembrane intracellular domain causing RET activation in familial medullary thyroid carcinoma

“…Deletions of variable regions of the gene, from 3 bp to 20 Kb, have been found in sporadic MTC (Kimura et al 1995, Hofstra et al 1996, Alemi et al 1997, Ceccherini et al 1997, Kalinin & Frilling 1998, Marsh et al 1998, Uchino et al 1999, Quadro et al 2001, while three different duplications (9 and 12 bp) and a 1 bp deletion/ 13 bp insertion, have been reported in MEN2A and FMTC families (Hoppner & Ritter 1997, Hoppner et al 1998, Pigny et al 1999, Ahmed et al 2005. Interestingly, all these variants are in frame, frequently involving deletion or insertions of Cys residues.…”