Molecular Basis and Natural History of Medullary Thyroid Cancer: It is (Almost) All in the RET

SIMPLE SUMMARY: Medullary thyroid carcinoma (MTC) is a rare neoplasm supported by a strong genetic determinism. This review summarizes the genetic landscape of MTC at both germline and somatic levels to understand the molecular basis and the natural history of the tumour, mainly but not exclusively, linked to RET proto-oncogene genetic abnormalities. RET is a tyrosine kinase receptor that represents a therapeutic target with encouraging results. However, some RET genetic variations could lead to treatment resistance. ABSTRACT: Medullary thyroid cancer (MTC) is a rare disease, which can be either sporadic (roughly 75% of cases) or genetically determined (multiple endocrine neoplasia type 2, due to REarranged during Transfection RET germline mutations, 25% of cases). Interestingly, RET pathogenic variants (mainly M918T) have also been reported in aggressive forms of sporadic MTC, suggesting the importance of RET signalling pathways in the pathogenesis of MTC. The initial theory of RET codon-related MTC aggressiveness has been recently questioned by studies suggesting that this would only define the age at disease onset rather than the aggressiveness of MTC. Other factors might however impact the natural history of the disease, such as RET polymorphisms, epigenetic factors, environmental factors, MET (mesenchymal–epithelial transition) alterations, or even other genetic alterations such as RAS family (HRAS, KRAS, NRAS) genetic alterations. This review will detail the molecular bases of MTC, focusing on RET pathways, and the potential mechanisms that explain the phenotypic intra- and interfamilial heterogeneity.