The Role of Epigenetic Alterations in Papillary Thyroid Carcinogenesis

Abstract

Papillary thyroid carcinoma (PTC) accounts for over 80% of all thyroid malignancies. The molecular pathogenesis remains incompletely clarified although activation of the RET fusion oncogenes, and RAS and BRAF oncogenes, has been well characterized. Novel technologies using genome-wide approaches to study tumor genomes and epigenomes have provided great insights into tumor development. Growing evidence shows that acquired epigenetic abnormalities participate with genetic alterations to cause altered patterns of gene expression/function. It has been established beyond doubt that promoter cytosine methylation in CpG islands, and the subsequent gene silencing, is intimately involved in cancer development. These epigenetic events very likely contribute to significant variation in gene expression profiling, phenotypic features, and biologic characteristics seen in PTC. Hypermethylation of promoter regions has also been analyzed in PTC, and most studies have focused on individual genes or a small cohort of genes implicated in tumorigenesis.

DNA Methylation Signatures Identify Biologically Distinct Thyroid Cancer Subtypes

“…Although aberrant genomic DNA methylation is a hallmark of cancer (29) and the genome-wide aberrant promoter DNA methylation patterns of many tumor types has been meticulously described (30 -32), data on aberrant DNA methylation in thyroid cancer are mainly restricted to single-copy candidate genes in specific tumor subtypes (33)(34)(35). In this study, we used DNA methylation arrays to determine, for the first time, the genome-wide promoter methylation status of primary papillary, follicular, medullary, and anaplastic thyroid tumors, nontumorigenic thyroid tissues, and 4 thyroid cancer cells lines.…”

Differential Diagnostic Ultrasound Criteria of Papillary and Follicular Carcinomas: A Multivariate Analysis

“…Whether FTC develops directly from follicular thyroid cells or from follicular adenomas is still a matter of scientific controversy [14,17]. In addition to the described mutations, epigenetic factors leading to gene activation or deactivation may play a role in the development of differentiated thyroid cancer and are co-determinants of the phenotypical appearance of PTC and FTC tumors [18]. These phenotypical manifestations are reflected in the ultrasound characteristics of the thyroid carcinomas.…”

Thyroid Tumors with Encapsulated Follicular Pattern : A Diagnostıc Dilemma

“…17,24,25 Identification of genetic and molecular pathogenesis of malignant thyroid lesions, including activation of some oncogenes, such as BRAF, have provided great insights into tumor development and differential diagnosis of malign lesions. 5 Many studies focused on gene expression profile of thyroid tumors and its practical role in early differential diagnosis of thyroid lesions. 5,26 Immunohistochemical markers have commonly been studied as diagnostic tool for differentiation of PC.…”

“…5 Many studies focused on gene expression profile of thyroid tumors and its practical role in early differential diagnosis of thyroid lesions. 5,26 Immunohistochemical markers have commonly been studied as diagnostic tool for differentiation of PC. For example, BRAF mutation is seen commonly in PC cases.…”

“…4 BRAF is a serine-threonine kinase signaling molecule, and mutations of BRAF leads to potential activation of MAP kinase/ERK pathway, which is the main pathway through which the majority of genetic alterations exert their oncogenic actions in thyroid cancer. 5 Activation of MAP kinase/ERK pathway stimulates tumor formation by upregulating cell division and proliferation. 6 BRAF mutation is seen in 35-67% of papillary carcinoma (PC) cases 7 , thus suggested to be used in differential diagnosis of PC.…”