Molecular pathogenesis and mechanisms of thyroid cancer

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Abstract
Thyroid cancer is a common endocrine malignancy, and exciting progress has occurred in recent years in understanding its molecular pathogenesis. Genetic and epigenetic alterations are the driving forces of thyroid cancer. Examples of these alterations include mutations in BRAF (BRAFV600E), RAS, PIK3CA, PTEN, TP53, β-catenin (CTNNB1), anaplastic lymphoma kinase (ALK) and isocitrate dehydrogenase 1 (IDH1), translocations (RET–PTC and paired box 8 (PAX8)–peroxisome proliferator-activated receptor-γ (PPARG)) and aberrant gene methylation. At the core of the molecular pathogenesis of thyroid cancer is the uncontrolled activity of various signalling pathways, including the MAPK, PI3K–AKT, nuclear factor-κB (NF-κB), RASSF1–mammalian STE20-like protein kinase 1 (MST1)–forkhead box O3 (FOXO3), WNT–β-catenin, hypoxia-inducible factor 1α (HIF1α) and thyroid-stimulating hormone (TSH)–TSH receptor (TSHR) pathways. The progression of thyroid cancer is a process of accumulation of genetic and epigenetic alterations with corresponding progressive derangements of signalling pathways. These are accompanied by numerous secondary molecular alterations, both in the cell and in the tumour microenvironment, which, acting in cooperation, amplify and synergize their impacts on thyroid tumorigenesis. Aberrant silencing of thyroid iodide-handling genes and consequent loss of radioiodine avidity of thyroid cancer promoted by BRAF-V600E is a unique molecular pathological process in thyroid cancer, which causes the failure of radioiodine treatment. The recent molecular findings provide unprecedented opportunities for further research and clinical development of novel molecular-based treatment strategies for thyroid cancer.