N-ras Mutation in Poorly Differentiated Thyroid Carcinomas: Correlation with Bone Metastases and Inverse Correlation to Thyroglobulin Expression

Abstract

Codon 61 of the N-ras oncogene was screened for mutations in 99 surgically resected thyroid carcinomas by a polymerase chain resection (PCR)-based method (PCR-primer introduced restriction with enrichment of mutant alleles [PCR-PIREMA]). A point mutation of the N-ras oncogene at the codon 61 was detected in 16 of 99 (16.2%) thyroid carcinomas examined by this method. No RAS alteration was detected in the group of 11 medullary thyroid carcinomas, while 3 of 31 (10.0%) papillary carcinomas, 2 of 5 (40%) follicular carcinomas, 8 of 44 (18.2%) poorly differentiated carcinomas, and 3 of 5 (60%) undifferentiated carcinomas showed an activation of N-RAS proto-oncogene. Interestingly, two primary follicular tumors and their corresponding bone metastases, showed N-ras mutations. In the same cases we evaluated the expression of thyroglobulin by immunohistochemical analysis. Although the majority of well-differentiated carcinomas expressed a high level of thyroglobulin, the expression of the same antigen was absent or only occasional weakly positive in 33 of 44 poorly differentiated carcinomas. Interestingly, N-ras mutation was restricted to the group of tumours with low or absent thyroglobulin expression, suggesting that this genetic change is prevalent in less differentiated tumors.

An update on molecular biology of thyroid cancers

“…Studies on RAS mutation in different types of thyroid cancer have shown that these mutations are observed in both malignant and benign types of tumors [97]. However, codon 61 point mutations have been especially reported to cause tumor progression in an aggressive manner [98,99].…”

“…In PTCs, RAS mutations are found at relatively low frequencies, in approximately 10% of tumors. In follicular thyroid carcinomas, 40-50% of tumors carry RAS mutations [87,91,96], which may correlate with poor prognosis and tumor dedifferentiation [97,240]. RAS mutations may influence tumor dedifferentiation, as they are found with high frequency in ATCs.…”

Novel Approaches in Anaplastic Thyroid Cancer Therapy

“…RAS mutation, although most significant in the diagnosis of follicular thyroid cancer (FTC), is also reported in papillary thyroid cancer (PTC) and ATC [35,36]. From studies of different histological types of thyroid cancer, up to 60% of ATC was found to harbor RAS mutation [36][37][38]. In a stepwise process, RAS appeared to be an "early-stage" mutation.…”

Poorly Differentiated Thyroid Carcinoma: 5 Years after the 2004 WHO Classification of Endocrine Tumours

“…Several molecular alterations have been investigated to define PDTC histogenesis, but the molecular genetic data so far reported in the literature reflect the heterogeneity of the case series analyzed, as the result of the discrepancies in PDTC diagnosis and classification. Generally, irrespective of the selection criteria applied, RAS point mutations appear to be a common molecular alteration in these tumors, although they were found with highly variable frequency and wide variation in specific types of RAS mutations [4,28,29]. Likewise, BRAF mutations were detected in poorly differentiated carcinomas having residual papillary carcinoma foci [30, 31], but not in cases lacking the morphologic evidence of transition from well differentiated papillary to poorly differentiated carcinoma [32].…”