Genome-wide profiling identifies the THYT1 signature as a distinctive feature of widely metastatic Papillary Thyroid Carcinomas
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Greta Gandolfi1, Moira Ragazzi2, Dario de Biase3, Michela Visani4, Eleonora Zanetti2, Federica Torricelli1, Valentina Sancisi1, Mila Gugnoni1, Gloria Manzotti1, Luca Braglia5, Silvio Cavuto5, Domenico Franco Merlo5, Giovanni Tallini4, Andrea Frasoldati6, Simonetta Piana2 and Alessia Ciarrocchi1
1Laboratory of Translational Research, Azienda Unità Sanitaria Locale di Reggio Emilia - IRCCS, Reggio Emilia 42123, Italy
2Pathology Unit, Department of Oncology, Azienda Unità Sanitaria Locale di Reggio Emilia - IRCCS, Reggio Emilia 42123, Italy
3Department of Pharmacology and Biotechnology (FaBiT), University of Bologna, 40139 Bologna, Italy
4Department of Medicine, Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale-DIMES, Anatomic Pathology Unit, Bellaria Hospital, University of Bologna, 40139 Bologna, Italy
5Research and Statistics Unit, Azienda Unità Sanitaria Locale di Reggio Emilia-IRCCS, Reggio Emilia, 42123, Italy
6Endocrinology Unit, Azienda Azienda Unitaria Sanitaria Locale di Reggio Emilia , Reggio Emilia 42123, Italy
Alessia Ciarrocchi, email: [email protected]
Keywords: papillary thyroid carcinomas; distant metastases; copy number alterations; next generation sequencing; TERT duplication
Received: September 14, 2017 Accepted: October 27, 2017 Published: December 01, 2017
Background: Papillary 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.
Results: We 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 Methods: A 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.
Conclusions: Overall 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.
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