A Narrative Review of Genetic Alterations in Primary Thyroid Epithelial Cancer

Abstract

Thyroid carcinoma is the most frequent endocrine neoplasia. Different types of thyroid carcinoma are described: well-differentiated papillary thyroid carcinoma (PTC), poorly differentiated thyroid carcinoma (PDTC), follicular thyroid carcinoma (FTC), anaplastic thyroid carcinoma (ATC), and medullary thyroid carcinoma (MTC). MTC is inherited as an autosomal dominant trait in 25% of cases. The genetic landscape of thyroid carcinoma has been largely deciphered. In PTC, genetic alterations have been found in about 95% of tumors: BRAF mutations and RET rearrangements are the main genetic alterations. BRAF and RAS mutations have been confirmed to play an important role also in PDTC and ATC, together with TP53 mutations that are fundamental in tumor progression. It has also been clearly demonstrated that telomerase reverse transcriptase (TERT) promoter mutations and TP53 mutations are present with a high-frequency in more advanced tumors, frequently associated with other mutations, and their presence, especially if simultaneous, is a signature of aggressiveness. In MTC, next-generation sequencing confirmed that mutations in the RET gene are the most common molecular events followed by H-RAS and K-RAS mutations. The comprehensive knowledge of the genetic events responsible for thyroid tumorigenesis is important to better predict the biological behavior and better plan the therapeutic strategy for specific treatment of the malignancy based on its molecular profile.

Keywords: BRAF; RET; TERT; molecular signature; oncogenes; p53; thyroid cancer.

Figure 1

Different histological types of thyroid carcinomas and most relevant/driver molecular alterations.

Figure 2

Mechanisms of RET/papillary thyroid carcinoma (PTC) activation. (A): the tyrosine kinase domain of the RET gene is constitutively activated by the fusion with a ubiquitous gene; (B): a paracentric inversion on chromosome 10 leads to the formation of a RET chimera as RET/PTC1 and RET/PTC3; (C): a chromosomal translocation leads to the formation of a RET chimera as RET/PTC2.

Figure 3

Schematic representation of TERT gene with the indication of the 2 most frequent mutations localized in the gene promoter, responsible for the transcription of the gene starting from the ATG codon.

Figure 4

RAS gene activation in cancer: The RAS oncogene encodes for the p21 protein. In its native state, p21 controls cell growth and differentiation. When a point mutation occurs at codons 12, 13 and 61, p21 is constitutively activated, leading to uncontrolled cell growth.

Figure 5

TP53 gene encodes for a protein involved in the control of the cell cycle. When DNA damage occurs, TP53 is able to induce the arrest of the cell cycle, and mutated cells cannot give origin to altered clones. Mutated TP53 loses the ability to stop the growth of mutated cells. Thus, tumoral clones take over.

Figure 6

Mechanisms of activation of the RET gene: in physiological conditions, the binding of a RET ligand, which is mediated by a co-receptor, induces the dimerization of two to RET molecules, causing the phosphorylation of the tyrosine kinase domain (A). When a point mutation in the cysteine domain is present, as it happens in multiple endocrine neoplasia (MEN) type 2A syndrome, the constitutive dimerization of 2 RET molecules occurs, and the receptor is activated independently by ligand-binding (B). Alternatively, if the mutation occurs in the tyrosine kinase domain, as it happens in MEN 2B syndrome, constitutive phosphorylation activates the RET receptor independently by ligand-binding (C).