RAS Mutations in Thyroid Cancer

Abstract

In recent years, our understanding of the genetic alterations underlying thyroid oncogenesis has greatly expanded. The use of molecular markers, including RAS, in the management of thyroid carcinoma is also increasing. This review summarizes the current literature surrounding RAS and discusses its potential as a diagnostic and prognostic indicator in the management of thyroid cancer. The Oncologist 2013;18:926 -932 Implications for Practice: In recent years, our understanding of the molecular mechanisms underlying thyroid oncogenesis has greatly expanded. Further, the use of some molecular markers in the clinical management of thyroid cancer is increasing. Mutations in RAS represent the second most common genetic event in thyroid neoplasia. However, the significance of RAS-positive mutation status and the biological behavior of thyroid carcinomas that harbor RAS are not completely understood. The purposes of this review are to clarify the current literature surrounding RAS mutations in thyroid cancer and to examine the potential utility of RAS as a diagnostic tool to predict the presence of malignancy, thus altering subsequent clinical management. In addition, the prognostic value of RAS positivity in predicting the risk for tumor aggressiveness, recurrence, and mortality is discussed. INTRODUCTIONThyroid cancer (TC) is the most common endocrine malignancy, and its incidence is on the rise [1]. Tumors of follicular epithelial cell origin account for the vast majority of these cancers, and of these, well-differentiated papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC) account for 95%; whereas, poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) are observed far less frequently [2]. In recent years, our understanding of the molecular mechanisms underlying thyroid oncogenesis has greatly expanded, thus enabling differentiation of thyroid tumors based on characteristic genetic alterations in addition to traditional histologic criteria [3]. The most clinically relevant markers to date include point mutations in BRAF and RAS and RET/PTC and PAX8/PPAR␥ rearrangements. PTC is known to harbor BRAF most commonly, followed by RAS and RET/PTC, whereas FTC is characterized by the presence of either RAS or PAX8/PPAR␥ [3][4][5][6].The use of these molecular markers in the management of thyroid carcinoma is increasing. BRAF is perhaps the most studied of the markers and has emerged as an important diagnostic and prognostic tool. For example, the finding of BRAF in a thyroid nodule with indeterminate cytology is associated with a PTC risk of nearly 100%, and further, patients with BRAF-positive PTC are more likely to have aggressive and recurrent disease [7][8][9][10][11]. Likewise, RAS represents the second most common genetic mutation in TC and was first implicated in thyroid neoplasia more than two decades ago [12]. Despite this, the significance of RAS-positive mutation status and the biological behavior of thyroid carcinomas that harbor RAS are still not completely und...

Outcomes and Prognostic Factors in Radioiodine Refractory Differentiated Thyroid Carcinomas

“…A prospective well-standardized study should provide more accurate information but would need decades to give a good overview of the survival of these patients. x Molecular-biology studies have analyzed the prognostic roles of molecular biomarkers in alterations to the mitogen-activated protein kinase or phosphatidylinositol 3-kinase-AKR T cell lymphoma pathways, or the Telomerase Reverse Transcriptasepromoter mutation [40,41]. However, few studies have reported on the molecular profile of RR disease [42,43].…”

DIAGNOSIS OF ENDOCRINE DISEASE: High-yield thyroid fine-needle aspiration cytology: an update focused on ancillary techniques improving its accuracy

“…Other molecular alterations, i.e. point mutation in the three RAS genes (H, K, and N), have also been implicated in the pathogenesis of thyroid carcinomas, but their specificity is lower than that of the previously mentioned markers, as these mutations have also been identified in quite a high percentage of FA (25). Among these mutations, codon 61 of the NRAS gene is the most frequently mutated site, and seems to be also associated with distant metastases (26,27).…”

ENDOCRINE TUMOURS: Genetic predictors of thyroid cancer outcome

“…RAS mutations are more prevalent and seem to be more relevant as a prognostic indicator in follicular patterned lesions (FVPTC, FTC and, namely, PDTC) than in cPTC (18). All of the three RAS genes (H, K and N-RAS) were shown to be mutated in both benign and malignant thyroid tumours but the frequency of the mutations is higher in FTC (36%), PDTC (55%) and UTC (52%) and more frequently affects the N-RAS gene (20).…”

“…RAS mutations are less prevalent in benign and malignant Hürthle cell tumours (5 and 11% respectively) than in their non-Hürthle cell counterparts and less prevalent in PTC (10%) than in FTC (25-30%) (7,20). Within PTC, RAS mutations are rare in its classic form, whereas in FVPTC, its prevalence falls within the range of other follicular patterned tumours (w25%) (6).…”