Multicentre Clinical Validation of the THYT1 Test for Predicting Distant Metastases in Papillary Thyroid Carcinoma

It has been recently demonstrated that papillary thyroid carcinomas (PTCs) that develop distant metastases are characterized by three genetic alterations: Chr1q^amp, TERT_locus^amp, TERT_promoter^mut. This signature, named THYT1, holds the potential as an early prognostic predictor to identify patients at risk for disease progression. To implement the use of this signature in clinical practice we first developed a droplet digital PCR approach for a faster and cost-effective detection of the THYT1 in PTCs, then we validated its performance in a retrospective monocentric case-control training cohort (N = 90) of PTCs and in a separated multicentric validation cohort (N = 143) of PTCs. We also investigated THYT1 feasibility in cytological pre-surgical thyroid smears. In the training set, THYT1 evaluation by ddPCR showed 93% rate of concordance with the THYT1 status previously determined and correctly identified THYT1-positive and THYT1-negative PTCs with a 96% sensitivity and a 92% specificity. In the validation cohort, THYT1 identified up to 80% of distantly metastatic PTCs and significantly correlated with reduced overall survival. THYT1 signature was effective in anticipating at diagnosis both synchronous and metachronous metastases in advance of up to 19 years. These data confirm that THYT1 is an easy-to-use, rapidly available prognostic test to help refining the selection of patients with indolent lesions that could be eligible for conservative treatment strategies.