Update on Fundamental Mechanisms of Thyroid Cancer

Abstract

The incidence of thyroid cancer (TC) has increased worldwide over the past four decades. TC is divided into three main histological types: differentiated (papillary and follicular TC), undifferentiated (poorly differentiated and anaplastic TC), and medullary TC, arising from TC cells. This review discusses the molecular mechanisms associated to the pathogenesis of different types of TC and their clinical relevance. In the last years, progresses in the genetic characterization of TC have provided molecular markers for diagnosis, risk stratification, and treatment targets. Recently, papillary TC, the most frequent form of TC, has been reclassified into two molecular subtypes, named BRAF-like and RAS-like, associated to a different range of cancer risks. Similarly, the genetic characterization of follicular TC has been proposed to complement the new histopathological classification in order to estimate the prognosis. New analyses characterized a comprehensive molecular profile of medullary TC, raising the role of RET mutations. More recent evidences suggested that immune microenvironment associated to TC may play a critical role in tumor invasion, with potential immunotherapeutic implications in advanced and metastatic TC. Several types of ancillary approaches have been developed to improve the diagnostic value of fine needle aspiration biopsies in indeterminate thyroid nodules. Finally, liquid biopsy, as a non-invasive diagnostic tool for body fluid genotyping, brings a new prospective of disease and therapy monitoring. Despite all these novelties, much work remains to be done to fully understand the pathogenesis and biological behaviors of the different types of TC and to transfer this knowledge in clinical practice.

Keywords: BRAF; RAS; RET; oncogenes; thyroid cancer.

Figure 1

The molecular pathogenesis of thyroid cancer involves dysregulation of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3 kinase (PI3K)/AKT pathways. Common activating mutations in the MAPK pathway include RET-PTC and NTRK rearrangements, and RAS and BRAF mutations. Common genetic alterations in the PI3K pathway include RAS mutations, PTEN mutations or deletions, PIK3K mutations or amplifications, and AKT1 mutations. PAX8-PPARG fusions are common in FTC. Activation of Wnt/b-catenin pathway, inactivating mutations in TP53, and activating mutations in TERT promoter are frequent in undifferentiated thyroid cancer.