Genomic alterations in thyroid cancer: biological and clinical insights

Tumours can arise from thyroid follicular cells if they acquire driver mutations that constitutively activate the MAPK signalling pathway. In addition, a limited set of additional mutations in key genes drive tumour progression towards more aggressive and less differentiated disease. Unprecedented insights into thyroid tumour biology have come from the breadth of thyroid tumour sequencing data from patients and the wide range of mutation-specific mechanisms identified in experimental models, in combination with the genomic simplicity of thyroid cancers. This knowledge is gradually being translated into refined strategies to stratify, manage and treat patients with thyroid cancer. This Review summarizes the biological underpinnings of the genetic alterations involved in thyroid cancer initiation and progression. We also provide a rationale for and discuss specific examples of how to implement genomic information to inform both recommended and investigational approaches to improve thyroid cancer prognosis, redifferentiation strategies and targeted therapies. Genomic data from patients with thyroid cancer, combined with information on mutation-specific mechanisms from experimental models, is transforming the thyroid cancer research field. This Review summarizes the genetic alterations involved in follicular cell-derived thyroid cancer initiation and progression and their biological and clinical implications. Most thyroid cancers are initiated by a single genomic alteration, typically or in RAS genes, which constitutively activate the MAPK signalling pathway.Driver mutations or in RAS genes determine multiple clinicopathological properties of thyroid tumours, including their histology, level of differentiation and routes for metastatic dissemination.Advanced thyroid cancers usually evolve from -driven or RAS-driven clones and become more aggressive and less differentiated via the acquisition of additional genomic alterations in specific genes.Preclinical models of thyroid cancers are valuable tools to understand the underlying mechanisms and biological consequences of pathogenic mutations, and to test novel therapeutic strategies.Genomic characterization is a useful tool to refine prognosis of patients with thyroid cancers and can predict their responses to strategies to induce redifferentiation for subsequent radioactive iodine treatment. mutation and or fusions are actionable alterations with matched drugs that are approved for the treatment of certain patients whose thyroid tumours have these genetic defects.