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  • Review Article
  • Published:

A comprehensive overview of the role of the RET proto-oncogene in thyroid carcinoma

Nature Reviews Endocrinology volume 12, pages 192–202 (2016)Cite this article

Subjects

Key Points

  • RET proto-oncogene alterations are crucial events for thyroid cancer development

  • Different mechanisms of RET activation, point mutations and gene rearrangements characterize medullary and papillary thyroid carcinoma

  • RET genetic screening is an important tool for the diagnosis of patients with medullary thyroid cancer and can assist in the presurgical diagnosis of papillary thyroid cancer

  • RET mutations are a very strong factor for poor prognosis in medullary thyroid cancer

  • RET/PTC rearrangements, especially RET/PTC3, are associated with the most aggressive histological variant of papillary thyroid cancer

  • The knowledge of tumour biology is crucial for the identification of drugs able to block tumour development

Abstract

The rearranged during transfection (RET) proto-oncogene was identified in 1985 and, very soon thereafter, a rearrangement named RET/PTC was discovered in papillary thyroid carcinoma (PTC). After this discovery, other RET rearrangements were found in PTCs, particularly in those induced by radiation. For many years, it was thought that these genetic alterations only occurred in PTC, but, in the past couple of years, some RET/PTC rearrangements have been found in other human tumours. 5 years after the discovery of RET/PTC rearrangements in PTC, activating point mutations in the RET proto-oncogene were discovered in both hereditary and sporadic forms of medullary thyroid carcinoma (MTC). In contrast to the alterations found in PTC, the activation of RET in MTC is mainly due to activating point mutations. Interestingly, in the past year, RET rearrangements that were different to those described in PTC were observed in sporadic MTC. The identification of RET mutations is relevant to the early diagnosis of hereditary MTC and the prognosis of sporadic MTC. The diagnostic and prognostic role of the RET/PTC rearrangements in PTC is less relevant but still important in patient management, particularly for deciding if a targeted therapy should be initiated. In this Review, we discuss the pathogenic, diagnostic and prognostic roles of the RET proto-oncogene in both PTC and MTC.

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Figure 1: Different modalities of activation of the RET receptor.
Figure 2: The genotype–phenotype correlation between RET proto-oncogene mutations and the three MEN2 syndromes.
Figure 3: The prevalence of RET somatic mutations in sporadic MTC.
Figure 4: Schematic representation of shorter and longer RET/PTC1 and RET/PTC3 rearrangements reported in papillary thyroid carcinoma.

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  1. Department of Clinical and Experimental Medicine, Endocrine Unit, University of Pisa, Via Paradisa 2, 56124, Pisa, Italy

    Cristina Romei, Raffaele Ciampi & Rossella Elisei

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Romei, C., Ciampi, R. & Elisei, R. A comprehensive overview of the role of the RET proto-oncogene in thyroid carcinoma. Nat Rev Endocrinol 12, 192–202 (2016). https://doi.org/10.1038/nrendo.2016.11

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