Tumor-Specific Mutations in the Tyrosine Kinase Domain of the RET Proto-Oncogene in Pheochromocytomas of Sporadic Type.

Abstract

Abstract.Sporadic pheochromocytomas, sporadic medullary thyroid carcinomas (MTCs), pheochromocytomas and/or MTCs in multiple endocrine neoplasia (MEN) 2A or 2B were screened for mutations in the tyrosine kinase domain of the RET proto-oncogene by direct sequencing of PCR-amplified products or sequencing subcloned DNAs from PCR-products. All tumors of 4 MEN 2B patients were confirmed to contain a heterozygous missense mutation at codon 918 (ATG-~ACG; Met-Thr) of the RET proto-oncogene as well as their leukocytes. The same tumor-specific mutations at codon 918 were also found in 5/16 (31%) sporadic pheochromocytomas.These results suggest that mutations of the RET proto-oncogene in its tyrosine kinase domain play a role not only as the predisposing gene for MEN 2B, but also as a tumorigenic factor for pheochromocytomas of sporadic type.

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

“…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]. In this study, codon 768 mutations were shown to be rare in sporadic pheochromocytomas in contrast to sporadic MTCs.…”

“…With respect to sporadic pheochromocytomas, we detected codon 918 mutations in 31% of sporadic pheochromocytomas [9]. In the present study, we analyzed sporadic pheochromocytomas and pheochromocytomas with neurofibromatosis 1 (NF1), MEN 2A, or MEN 2B for mutations of codon 768 of the RET proto-oncogene.…”

“…A missense mutation at codon 768 in the tyrosine kinase domain of the RET proto-oncogene was recently described in a family with FMTC, which does not have a cysteine codon mutation [8]. The same mutation was also detected in 40% of sporadic MTCs which do not have codon 918 mutations.With respect to sporadic pheochromocytomas, we detected codon 918 mutations in 31% of sporadic pheochromocytomas [9]. In the present study, we analyzed sporadic pheochromocytomas and pheochromocytomas with neurofibromatosis 1 (NF1), MEN 2A, or MEN 2B for mutations of codon 768 of the RET proto-oncogene.…”

RET and neuroendocrine tumors

“…The affected codons were cysteine at 634 (12 patients) and tyrosine at 791 (one patient), both of which are associated with MEN 2A/FMTC development, and most of the patients with RET germline mutations developed MTC during the follow-up period, indicating that clinically apparent sporadic pheochromocytomas associated with RET germline mutations might be part of undiagnosed MEN 2 [127]. Somatic RET mutations have also been detected in 0-31% of patients with sporadic pheochromocytoma, mostly at codon 918 [133][134][135].…”

Obvious mRNA and protein expression but absence of mutations of the RET proto-oncogene in parathyroid tumors

“…In sporadic MTCs and pheochromocytomas, codon 918 mutations were detected fre¬ quently (3,5,6), but mutations in the cysteine-rich region of the RET proto-oncogene were found to be rare (7,8). In sporadic MTCs and pheochromocytomas, codon 918 mutations were detected fre¬ quently (3,5,6), but mutations in the cysteine-rich region of the RET proto-oncogene were found to be rare (7,8).…”