RAS proto-oncogene in medullary thyroid carcinoma

Abstract

Medullary thyroid carcinoma (MTC) is a rare malignancy originating from the calcitonin-secreting parafollicular thyroid C cells. Approximately 75% of cases are sporadic. Rearranged during transfection (RET) proto-oncogene plays a crucial role in MTC development. BesidesRET, other oncogenes commonly involved in the pathogenesis of human cancers have also been investigated in MTC. The family of humanRASgenes includes the highly homologousHRAS,KRAS, andNRASgenes that encode three distinct proteins. Activating mutations in specific hotspots of theRASgenes are found in about 30% of all human cancers. In thyroid neoplasias,RASgene point mutations, mainly inNRAS, are detected in benign and malignant tumors arising from the follicular epithelium. However, recent reports have also describedRASmutations in MTC, namely inHRASandKRAS. Overall, the prevalence ofRASmutations in sporadic MTC varies between 0–43.3%, occurring usually in tumors with WTRETand rarely in those harboring aRETmutation, suggesting that activation of these proto-oncogenes represents alternative genetic events in sporadic MTC tumorigenesis. Thus, the assessment ofRASmutation status can be useful to define therapeutic strategies inRETWT MTC. MTC patients withRASmutations have an intermediate risk for aggressive cancer, between those withRETmutations in exons 15 and 16, which are associated with the worst prognosis, and cases with otherRETmutations, which have the most indolent course of the disease. Recent results from exome sequencing indicate that, besides mutations inRET,HRAS, andKRAS, no other recurrent driver mutations are present in MTC.