Clinical use of molecular data in thyroid nodules and cancer.

Over the past three decades, advances in the molecular genetics of thyroid cancer (TC) have been translated into diagnostic tests, prognostic markers and therapeutic agents. The main drivers in differentiated thyroid cancer (DTC) pathogenesis are single point mutations and gene fusions in components of the MAPK and PI3K/AKT pathways. Other important genetic alterations in the more advanced types of TC include TERT promoter, TP53, EIF1AX, and epigenetic alterations. Utilizing this knowledge, a number of molecular tests have been developed for cytologically indeterminate thyroid nodules. Currently, three commercially available tests are in use including a DNA/RNA-based test (ThyroSeq v.3), an RNA-based test (Afirma Gene Sequencing Classifier, GSC) and a hybrid DNA/miRNA test, ThyGeNEXT/ThyraMIR. These tests are mostly used to rule out malignancy in Bethesda III and IV thyroid nodules as they all have high sensitivities and negative predictive values. Their common use, predominantly in the United States, has resulted in a significant reduction in unnecessary thyroid surgeries for benign nodules. Some of these tests also provide information on the underlying molecular drivers of TC; this may support decision-making in initial TC management planning, although this practice has not yet been widely adopted. More importantly, molecular testing is essential in patients with advanced disease before using any specific mono-kinase inhibitor (e.g. selpercatinib for RET-altered TC), as these drugs are ineffective in the absence of a specific molecular target. This mini-review discusses the utilization of molecular data in the clinical management of patients with thyroid nodules and TC in these different clinical situations.