Gandolfi Greta, Ragazzi Moira, de Biase Dario, Visani Michela, Zanetti Eleonora, Torricelli Federica, Sancisi Valentina, Gugnoni Mila, Manzotti Gloria, Braglia Luca, Cavuto Silvio, Merlo Domenico Franco, Tallini Giovanni, Frasoldati Andrea, Piana Simonetta, Ciarrocchi Alessia
Laboratory of Translational Research, Azienda Unità Sanitaria Locale di Reggio Emilia - IRCCS, Reggio Emilia 42123, Italy.
Pathology Unit, Department of Oncology, Azienda Unità Sanitaria Locale di Reggio Emilia - IRCCS, Reggio Emilia 42123, Italy.
Oncotarget. 2017 Dec 1;9(2):1813-1825. doi: 10.18632/oncotarget.22805. eCollection 2018 Jan 5.
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.
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.
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.
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.
甲状腺乳头状癌（PTC）通常是惰性肿瘤。然而，一小部分但比例显著的PTC具有侵袭性，会发展为弥漫性转移扩散并导致患者死亡。缺乏可靠的预测这些肿瘤转移行为的标志物阻碍了基于风险的疾病正确分层，从而导致患者过度治疗的问题。在本研究中，我们旨在确定与PTC远处转移发展相关的基因特征。
我们发现远处转移的PTC具有中等程度的拷贝数改变，但微卫星不稳定性水平低且突变负担低。我们确定1号染色体长臂重复、包含端粒酶逆转录酶（TERT）基因座的5号染色体短臂重复以及TERT启动子突变是远处转移PTC的独特特征。这三个基因变量定义了一个特征（THYT1），该特征与转移行为和缩短的生存期显著相关。我们在PTC细针穿刺活检（FNAB）中分析了THYT1特征，并证明了该特征作为PTC术前诊断环境中的分子标志物的适用性。
检索了1978年至2015年期间在意大利圣玛丽亚诺瓦综合医院 - IRCCS诊断的连续2937例甲状腺恶性肿瘤，以找出发生远处转移的患者（n = 50）。我们进行了深入分析以探索这些肿瘤的基因组格局。
总体而言，我们的数据确定了第一个独立预测PTC转移和不良结局的基因特征，并为将THYT1作为预后标志物以改善基于风险的PTC患者分层和管理的可能应用奠定了基础。
