MET Receptor Tyrosine Kinase Sequence Alterations in Differentiated Thyroid Carcinoma

Abstract

Activating mutations affecting the MET receptor tyrosine kinase are present in several types of human cancer, particularly in papillary renal cell carcinoma. Papillary thyroid carcinomas commonly express high levels of MET mRNA and protein, suggesting that increased MET signaling may be of importance in the molecular pathogenesis of differentiated thyroid carcinoma. To evaluate the role of MET mutations in thyroid carcinoma, we screened MET exons 2 to 21 for mutations in sporadic papillary, follicular, medullary, and anaplastic thyroid carcinomas using denaturing high-performance chromatography. A missense MET sequence alteration T1010I, located in exon 14 encoding for the juxtamembrane domain of MET, was found in 6 (6%) of the 104 thyroid carcinomas examined, whereas all 92 goiter samples had wild-type exon 14 (P = 0.031). Three (6%) of the 53 papillary, 2 (10%) of the 21 follicular, 1 (8%) of the 13 medullary, and none of the 17 anaplastic carcinomas studied had MET(T1010I). Four of the 6 T1010I sequence alterations were present also in the germline. MET protein expression showed no apparent association with the presence of MET(T1010I), and the clinical features of the patients with cancer with MET(T1010I) were similar to those of patients whose cancer did not harbor MET(T1010I). We conclude that MET(T1010I) sequence alteration is relatively frequent in differentiated thyroid carcinoma. The clinical and the molecular pathologic significance of this MET sequence alteration is not known.

MET exon 14 juxtamembrane splicing mutations: clinical and therapeutical perspectives for cancer therapy

“…All the cases were characterized by a missense mutation, which was a base substitution in the codon 1010 (T1010I) of exon 14. According to previously evidence (22), T1010I mutation induces oncogenic characteristics in tumor cell lines and therefore the presence of this alteration in thyroid cancer patients, even if it does not produce a JM-missing variant, might be considered as a MET exon 14 actionable mutation rather than a single nucleotide polymorphism (90).…”

Targeted therapies for thyroid tumors

“…80 The inhibitory activity against C-MET, the cognate receptor for the hepatocyte growth factor, may provide additional synergistic benefit in thyroid carcinomas, given the enhanced expression of the receptor observed in PTC and MTC. [81][82][83] An ongoing phase I dose-escalation study has examined the safety and pharmacokinetics of XL184 in patients with metastatic solid malignancies, with an expansion cohort limited to MTC. 84 A total of 15 MTC patients (44%) had achieved at least 30% reduction in tumor measurements, with 10 (29%) having confirmed partial responses.…”

Understanding Melanocyte Transformation – A Work in Progress

“…It has been identified as a part of the oncogenic fusion protein TRP-MET with mutations identified in multiple tumor types including renal papillary carcinoma, lung cancer, thyroid cancer, lymphoma and melanoma Park, Dean et al 1987;Natali, Nicotra et al 1993;Schmidt, Junker et al 1998;Ma, Jagadeeswaran et al 2005;Wasenius, Hemmer et al 2005;Tjin, Groen et al 2006). In melanoma, c-Met expression was undetectable in benign nevi, detectable in a small fraction of primary melanomas and significantly expressed in metastatic melanoma lesions (Natali, Nicotra et al 1993).…”