Specific Pattern of RAS Oncogene Mutations in Follicular Thyroid Tumors

Abstract

The prevalence of H-RAS, K-RAS, and N-RAS gene mutations in thyroid tumors according to malignancy and histology is controversial. Differences in methodology and histological classifications may explain discrepant results. To address this issue, we first performed a pooled analysis of 269 mutations garnered from 39 previous studies. Mutations proved significantly less frequent when detected with direct sequencing than without (12.3% vs. 17%). The rate of mutation involving N-RAS exon 1 (N1) and K-RAS exon 2 (K2) was less than 1%. Mutations of codon 61 of N-RAS (N2) were significantly more frequent in follicular tumors (19%) than in papillary cancers (5%) and significantly more frequent in malignant (25%) than in benign (14%) tumors. H-RAS mutations in codons 12/13 (H1) were found in 2-3% of all types of tumors, but H-RAS mutations in codon 61 (H2) were observed in only 1.4% of tumors, and almost all of them were malignant. K-RAS mutations in exon 1 were found more often in papillary than follicular cancers (2.7% vs. 1.6%) and were sometimes correlated with special epidemiological circumstances. The second part of this study involved analysis of 80 follicular tumors from patients living in Marseille (France) and Kiev (Ukraine). We used direct sequencing after PCR amplification of exons 1 and 2 of the three RAS genes. Common and atypical adenomas were separated using strict cytological criteria. Mutations of H1-RAS were found in 12.5% of common adenomas and one follicular carcinoma (2.9%). Mutations of N2-RAS occurred in 23.3% and 17.6% of atypical adenomas and follicular carcinomas, respectively. These results confirm the predominance of N2-RAS mutations in thyroid follicular tumors and their correlation with malignancy. They support the implication of N2-RAS mutations in the malignant progression of thyroid follicular tumors and the assumption that some atypical adenomas are precursors of follicular carcinomas.

Impairment of the p27kip1 function enhances thyroid carcinogenesis in TRK-T1 transgenic mice

“…As far as ras genes are concerned, mutations of codon 61 of N-RAS (N2) were significantly more frequent in follicular tumors (19%) than in papillary cancers (5%). H-RAS mutations in codons 12/13 (H1) were found in 2-3% of all types of thyroid tumors, but H-RAS mutations in codon 61 (H2) were observed in only 1.4% of tumors (Vasko et al 2003). K-RAS mutations in exon 1 were found more often in papillary carcinomas (De Micco 2003).…”

A High-Resolution Melting Protocol for Rapid and Accurate Differential Diagnosis of Thyroid Nodules

“…BRAF mutations are associated with poor clinical prognosis due to extrathyroid invasion and higher risk of relapse and metastasis. 19 Mutations in the family of RAS oncogenes, which encode for G-proteins that also convey signals to the MAPK pathway, are more common in follicular carcinomas (FTC) 20 and in follicular variant of papillary carcinoma (fvPTC). 21 Point mutations in the HRAS, KRAS, and NRAS genes are associated with specific domains of the protein and are able either to increase its affinity for substrate (substitution in residues 12 and 13) or to inactivate the autocatalytic GTPase function (residue 61).…”

Thyroid targeting of the N-ras(Gln61Lys) oncogene in transgenic mice results in follicular tumors that progress to poorly differentiated carcinomas

“…Between 20 and 50% of FTC are positive for ras mutations (Tallini, 2002). The N-ras mutation in codon 61 is the most frequent ras mutation in FTC and it is more frequent in malignant than in benign thyroid tumors (Motoi et al, 2000;Garcia-Rostan et al, 2003;Nikiforova et al, 2003b;Vasko et al, 2003;Zhu et al, 2003).…”