PRECISE: A prognostic thyrocyte-derived gene signature for papillary thyroid carcinoma

Purpose: Papillary thyroid carcinoma (PTC) exhibits heterogeneous behavior, underscoring the need for effective biomarkers and improved risk stratification methods. We developed a thyrocyte–derived gene signature, Prognostic RNA Expression Cell-specific Integrated SignaturE (PRECISE), using single-cell and single-nucleus RNA sequencing (RNAseq) and evaluated its prognostic utility across cohorts. Patients and Methods: PRECISE was developed using a discovery cohort of PTC patients (MDACC n=109, median follow-up=14 years). Within the cohort, 11 PTC tumors and 4 normal thyroid samples were successfully sequenced using single-nucleus RNAseq. Differentially expressed genes were integrated with previously identified thyrocyte-associated genes from single-cell RNAseq. Prognostic significance was assessed using bulk RNAseq in the discovery cohort and validated in 2 additional cohorts (VUMC n=65; TCGA n=370). A rank-based single-sample method was used for score calculation. Associations between PRECISE and progression-free (PFS) and disease-specific survival (DSS) were evaluated using multivariate Cox models, and predictive models were compared using Harrell’s C-statistic and likelihood ratio tests. Results: PRECISE comprised of 41 epithelial genes downregulated in PTC tumor cells. Higher PRECISE was significantly associated with shorter PFS across all 3 cohorts (MDACC HR=1.64, P=0.002; VUMC HR=2.54, P<0.001; TCGA HR=1.63, P=0.012) and remained significant after TNM stage adjustment in two cohorts with ≥5 years follow-up (MDACC aHR=1.42, P=0.038; VUMC aHR=2.12, P=0.024). PRECISE was also associated with DSS in these cohorts (MDACC HR=4.16, P<0.001; VUMC HR=2.23, P=0.010). Incorporating PRECISE significantly improved predictive performance for PFS and DSS beyond stage-based models. Conclusions: PRECISE is a thyroid-epithelial gene signature with independent prognostic value in PTC.