Study of BRAF and RAS Mutations in Thyroid Nodules with Indeterminate Cytology and Papillary Thyroid Cancer

Abstract

OBJECTIVES Thyroid cancer Treatment decision-making is often guided by tumor tissue molecular analysis. The aim of this study was the detection of BRAF, NRAS and HRAS mutations in Georgian patients with thyroid cancer and determination of the frequency of these mutations in the respective populations. SETTING Diagnostic molecular laboratory located in Tbilisi, Georgia. PARTICIPANTS 116 patients with thyroid cancer participated in the study. PRIMARY AND SECONDARY OUTCOME MEASURES Genetic change is the main force of thyroid tumor development, based on new methods of managing thyroid cancer. The latest significant genetic discovery in thyroid cancer is the BRAF-T1799A (V600E) transformation (the gene for B-type RAF kinase, BRAF). Since the initial report of this breakthrough in thyroid cancer years ago, rapid progress has been made. The BRAF mutation is the most common genetic change in thyroid cancer. BRAF and NRAS mutations are frequent genetic alterations found in thyroid nodules. These molecular markers establish a differential diagnosis and facilitate clinical decision-making. Prevalence of thyroid nodule-associated mutations has not been studied in Georgia. We evaluated BRAF, NRAS and HRAS mutations in Georgian patients with indeterminate cytology or diagnosed with papillary thyroid cancer (PTC). RESULTS BRAF (V600E), NRAS (G12C, G12D, Q61R, and Q61K) and HRAS (G12C, G13R, and Q61R) were determined in the DNA extracted from fine needle aspirate specimens. In total, 116 patient samples were analyzed using competitive-specificTaqMan PCR (Cast PCR TM). In these samples, 36 were diagnosed as papillary thyroid carcinoma, and 80 were indeterminate by Bethesda system for reporting thyroid cytopathology (BSRTC III-V). BRAF (V600E) mutation was the most frequent genetic alteration found in 31% of all analyzed samples. Specifically, this mutation was present in 61% of PTC cases and 18% of cases classified as indeterminate (BSRTC III-V). NRAS mutations were present in 16% of PTC and 30% of indeterminate cytology samples. NRAS G12D and Q61R were most prevalent at 36.6% and 40% of all NRAS mutations. BSRTC IV category of indeterminate cytology had the highest frequency of NRAS mutations at 43%. From analyzed samples, HRAS (Q61R) mutation was present in only one PTC case.