Genetic Alterations in Poorly Differentiated and Undifferentiated Thyroid Carcinomas

Abstract

Thyroid gland presents a wide spectrum of tumours derived from follicular cells that range from well differentiated, papillary and follicular carcinoma (PTC and FTC, respectively), usually carrying a good prognosis, to the clinically aggressive, poorly differentiated (PDTC) and undifferentiated thyroid carcinoma (UTC).It is usually accepted that PDTC and UTC occur either de novo or progress from a pre-existing well differentiated carcinoma through a multistep process of genetic and epigenetic changes that lead to clonal expansion and neoplastic development. Mutations and epigenetic alterations in PDTC and UTC are far from being totally clarified. Assuming that PDTC and UTC may derive from well differentiated thyroid carcinomas (WDTC), it is expected that some PDTC and UTC would harbour genetic alterations that are typical of PTC and FTC. This is the case for some molecular markers (BRAF and NRAS) that are present in WDTC, PDTC and UTC. Other genes, namely P53, are almost exclusively detected in less differentiated and undifferentiated thyroid tumours, supporting a diagnosis of PDTC or, much more often, UTC. Thyroid-specific rearrangements RET/PTC and PAX8/PPARγ, on the other hand, are rarely found in PDTC and UTC, suggesting that these genetic alterations do not predispose cells to dedifferentiation. In the present review we have summarized the molecular changes associated with the two most aggressive types of thyroid cancer.

Frequency of TERT promoter mutations in human cancers

“…No mutations were detected in medullary thyroid carcinomas, as described by Killela et al 3 , nor in normal thyroid and benign lesions, such as goitre, adenomas or thyroiditis; this finding fits with previous studies that reported telomerase expression in malignant lesions and not in normal tissue or hyperplastic lesions 8,9 . TERT mutations were associated with clinicopathological features (older age, increased tumour size and a b male gender), but, after histotype stratification, these associations were only maintained in cPTC.…”

Telomerase promoter mutations in cancer: an emerging molecular biomarker?

“…In line with this, telomerase activity in normal thyroid samples is almost absent, being detected in less than 7 % of cases [16,114]. On the other hand, telomerase activity was consistently reported in a specific population of thyroid cells-the solid cell nests (SCNs) which are considered to represent embryonic remnants of the ultimobranchial body [95,101].…”

Treatment of advanced thyroid cancer with targeted therapies: ten years of experience

“…In PDTCs, beta-catenin (CTNNB1), p53, and BRAF V600E mutations can be also present. Although the most common oncogene alteration in ATCs are p53 point mutations, BRAF V600E , PIK3CA, PTEN, IDH1, and ALK mutations have all been reported in these aggressive thyroid tumors, in which, unlike in other hystotypes, it is not uncommon to have multiple genetic alterations in the same tumoral tissue (Eng et al 1996, Smallridge et al 2009, Soares et al 2011.…”

“…Despite the many genetic alterations that have been described for thyroid cancer and the most recent efforts to find other activated oncogenes, approximately 5-10% of PTCs, 50-60% of MTCs, and 10% of ATCs and PDTCs are still negative for all known genetic abnormalities (Soares et al 2011, Giordano et al 2014, Ji et al 2015.…”