NRAS codon 61 mutation is associated with distant metastasis in patients with follicular thyroid carcinoma

Abstract

Background: Known factors related to distant metastases in follicular thyroid carcinoma (FTC) included age, primary tumor size, and invasiveness. Distant metastasis is a main cause of death in FTC patients. Several studies showed that the presence of RAS mutations is also associated with poor clinical outcomes. We analyzed RAS mutations in FTC with distant metastases, FTC without a distant metastasis, follicular adenoma (FA), and nodular hyperplasia (NH). Furthermore, we elucidated the relationship between RAS mutations and clinical outcomes in FTC patients.

Methods: We selected patients who underwent a thyroidectomy for FTC with distant metastases (n=28), size matched FTC specimens without a distant metastasis (n=28), FA (n=17), and NH (n=12). NRAS, HRAS, and KRAS mutations were assessed using direct sequencing.

Results: Among 85 patients, 39 patients (46%) had RAS mutations. The NRAS codon 61 mutation (n=21; 25%) was the most common point mutation. HRAS codon 61, KRAS codon 12/13, and KRAS codon 61 mutations were found in 7, 6, and 4 patients, respectively. A NRAS codon 12/13 mutation was found in only 1 patient, and a HRAS codon 12/13 mutation was not found. RAS mutations were significantly more common in the FTC than FA or NH groups. Especially, the NRAS codon 61 mutation was associated with distant metastasis in patients with FTC.

Conclusions: The presence of a RAS mutation, especially a NRAS codon 61 mutation, was significantly associated with the distant metastasis. The NRAS codon 61 mutation status might be a potential prognostic factor in FTC patients.

FIG. 1.

RAS mutation frequencies in study groups using three kinds of RAS mutation analyses (six codons, three codons, and single codon). ^aAnalysis of RAS mutation frequency between FTC group and FA or NH groups. FTC had significantly more RAS mutations than FA or NH groups in all three kinds of RAS mutation analyses (six codons, three codons, and single codon). ^bAnalysis of RAS mutation frequency between FTC M1 and FTC M0 groups. Only NRAS codon 61 mutation had a significant association with FTC M1 group. NH, nodular hyperplasia (n=12); FA, follicular adenoma (n=17); FTC, follicular thyroid carcinoma; FTC M0, FTC without a distant metastasis (n=28); FTC M1, FTC with distant metastases (n=28).

FIG. 2.

Survival analysis of FTC patients. (A) Overall survival in the FTC patients according to the RAS mutation status. There was no difference in the overall survival between RAS mutant FTC and wild-type FTC patients. (B) Overall survival in the FTC patients according to NRAS codon 61 mutation status demonstrated no difference between NRAS codon 61 mutant-FTC and NRAS codon 61 wild-type FTC patients.

FIG. 3.

Distribution of metastatic sites in follicular thyroid carcinoma with distant metastases. Metastatic disease at one site (lung or bone only) was more significantly associated with RAS mutations than metastatic disease at two or more sites (both lung and bone, or multiple sites).