PRECISE: A Prognostic Thyrocyte-Derived Gene Signature for Papillary Thyroid Carcinoma.

PURPOSEPapillary 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 RNA sequencing (scRNA-seq) and single-nucleus RNA sequencing (snRNA-seq) and evaluated its prognostic utility across cohorts.

EXPERIMENTAL DESIGNPRECISE was developed using a discovery cohort of patients with PTC [MD Anderson Cancer Center (MDACC), n = 109, median follow-up = 14 years]. Within the cohort, 11 PTC tumors and 4 normal thyroid samples were successfully sequenced using snRNA-seq. Differentially expressed genes were integrated with previously identified thyrocyte-associated genes from scRNA-seq. Prognostic significance was assessed using bulk RNA-seq in the discovery cohort and validated in two additional cohorts [Vanderbilt University Medical Center (VUMC), n = 65; The Cancer Genome Atlas (TCGA), n = 370]. A rank-based single-sample method was used for score calculation. Associations between PRECISE and progression-free survival (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.

RESULTSPRECISE is comprised of 41 epithelial genes downregulated in PTC tumor cells. Higher PRECISE was significantly associated with shorter PFS across all three cohorts [MDACC: hazard ratio (HR) = 1.64, P = 0.002; VUMC: HR = 2.54, P < 0.001; TCGA: HR = 1.63, P = 0.012] and remained significant after tumor-node-metastasis stage adjustment in two cohorts with ≥5 years of follow-up [MDACC adjusted HR (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.

CONCLUSIONSPRECISE is a thyroid epithelial gene signature with independent prognostic value in PTC.