N-ras mutation: an independent prognostic factor for aggressiveness of papillary thyroid carcinoma.

Abstract

The clinical importance of point mutations of ras oncogene in differentiated thyroid cancers has not been fully clarified. The purpose of this study is to determine the prognostic importance of ras mutation in papillary thyroid carcinoma. Tumors of 91 patients with papillary carcinoma were studied; mean follow-up was 14.1 years (range, 1 to 40 years). Patients were grouped as follows: class I, intrathyroidal disease, n = 21; class II, cervical node metastases, n = 22; class III, extrathyroidal disease, n = 19; and class IV, distant metastases, n = 29. DNA was analyzed with polymerase chain reaction, oligonucleotide hybridization, and DNA sequence analysis techniques. Thirteen (14.3%) of 91 tumors showed an N-ras point mutation: 4.8% (1 of 21) patients in class I; 4.5% (1 of 22) patients in class II; 15.8% (3 of 19) patients in class III; and 27.8% (8 of 29) patients in class IV. Each mutation changed codon 61 from glutamine to arginine. Patients with distant metastases (8 of 29) had a significantly higher incidence of ras mutations than others (5 of 62, p = 0.01). Patients in classes III and IV also had a higher incidence of mutations (11 of 48) than patients in classes I and II (2 of 43, p = 0.01). The incidence of ras mutations was significantly higher in patients who died of papillary cancer (5 of 15, 33.3%) than in patients who are still alive (8 of 76, 10.5%) (p = 0.02). Kaplan-Meier survival curves also showed a greater mortality from tumor (p < 0.05) and a higher recurrence rate (p < 0.01) in ras-positive tumors than in the ras-negative group. Finally, in studies by multivariate analyses, positive ras mutation and age were shown to be two independent prognostic factors for prediction of death from papillary cancer and recurrence of cancer. Mutation of N-ras gene at codon 61 is an independent prognostic factor for aggressiveness of papillary thyroid carcinomas.