Genome-wide profiling identifies the THYT1 signature as a distinctive feature of widely metastatic Papillary Thyroid Carcinomas

Abstract

BackgroundPapillary Thyroid Carcinomas (PTCs) are generally indolent tumors. However, a small but significant percentage of PTCs behaves aggressively, progressing to a diffuse metastatic spreading and leading to patient's death. The lack of reliable markers for predicting the metastatic behavior of these tumors prevents a correct risk based stratification of the disease, thus contributing to the issue of patients’ overtreatment. In this study we aimed at identifying genetic features associated with the development of distant metastasis in PTCs.ResultsWe showed that DM PTCs are characterized by a moderate degree of copy number alterations but display low level of microsatellite instability and a low mutational burden. We identified duplication of Chr1q, duplication of Chr5p harboring the TERT genomic locus and mutations of TERT promoter as distinctive features of DM PTCs. These three genetic variables defined a signature (THYT1) that was significantly associated with a metastatic behavior and a shortened survival. We analyzed the THYT1 signature in PTCs fine needle aspirate biopsies (FNAB) and we demonstrating the applicability of this signature as a molecular marker in the pre-operative diagnostic setting of PTCs.Materials and MethodsA consecutive series of 2,937 thyroid malignancies, diagnosed at the Arcispedale S. Maria Nuova - IRCCS, Italy between 1978 and 2015 were searched to retrieve those who developed distant metastasis (DM, n = 50). We performed a deep profiling to explore the genomic landscape of these tumors.ConclusionsOverall our data identify the first genetic signature that independently predicts metastasis and negative outcome of PTCs, and lay the basis for the possible application of the THYT1 as prognostic marker to improve risk-based stratification and management of PTC patients.

Immunomorphology and molecular biology of mixed primary liver cancers: is Nestin a marker of intermediate‐cell carcinoma?

“…Mutations in the TERT promoter were described as associated with aggressive behaviour in different cancers, including glioblastoma and thyroid cancers. 26,27 TP53 was mutated in intermediate and in HCC areas, but not in iCC areas. On the contrary, altered TERT promoter mutations were found in all three components of cHCC-CC.…”

“…TP53 is a keeper of genomic stability and its altered activity could be linked with different types of cancer. Mutations in the TERT promoter were described as associated with aggressive behaviour in different cancers, including glioblastoma and thyroid cancers . TP53 was mutated in intermediate and in HCC areas, but not in iCC areas.…”

Whole-Exome Sequencing of Matched Primary and Metastatic Papillary Thyroid Cancer

“…Other genes reported to play a role in metastatic behavior of PTCs include TERT, ATM, RAS, and RET/PTC (8,(56)(57)(58). Gandolfi et al in their study of metastatic PTC found that the THYT1 genetic signature, comprising of duplications in chromosomal regions 1q and 5p (harboring the TERT genomic locus), and TERT promoter mutations, was a highly specific marker of distant metastasis in PTCs (59).…”

Molecular Diagnostic of Solid Tumor Using a Next Generation Sequencing Custom-Designed Multi-Gene Panel

“…TP53 gene is tested when a diagnosis of anaplastic or poorly differentiated thyroid carcinoma is being considered [2,18]. EIF1AX, MED12, MET, PIK3CA, PTEN, and TERT target regions are also analyzed for diagnostic/prognostic purposes [2,[17][18][19][20][21][22][23]. Somatic RET gene mutations leading to protein constitutive activation are evaluated in medullary carcinomas according to Wells et al [11].…”