JCO Precis Oncol. 2026 Jul;10(7):e2600207. doi: 10.1200/PO-26-00207. Epub 2026 Jul 23.
ABSTRACT
PURPOSE: Loss of thyroid differentiation underlies the aggressive behavior of a subset of papillary thyroid carcinomas (PTCs). The Thyroid Differentiation Score (TDS), introduced by The Cancer Genome Atlas (TCGA), quantifies tumor differentiation but has limited reproducibility and clinical applicability. We developed and validated a revised score (xTDS) that enables reproducible assessment of tumor differentiation with prognostic relevance across cohorts.
METHODS: We analyzed RNA sequencing data from 570 patients with PTC across three independent cohorts: a discovery cohort from the MD Anderson Cancer Center (n = 111) and two external validation cohorts from Vanderbilt University (n = 69) and TCGA (n = 390). xTDS was evaluated for correlation with the original TDS, association with oncogenic drivers, and prognostic value for disease-specific survival (DSS) and progression-free survival (PFS).
RESULTS: xTDS showed near-perfect correlation with the original TDS (Spearman ρ = 0.98) and recapitulated known biological patterns, with BRAF V600E-driven tumors exhibiting the lowest differentiation scores and RAS-driven tumors the highest across all cohorts (P < .001). Low xTDS was associated with worse DSS in the MD Anderson (P < .001) and Vanderbilt (P = .005) cohorts and showed a similar numerical trend in TCGA, without statistical significance because of limited events. Low xTDS was consistently associated with worse PFS across all three cohorts (P = .048, <0.001, and 0.007, respectively).
CONCLUSION: xTDS is a reproducible measure of thyroid differentiation that preserves the biological and prognostic relevance of the original TDS while overcoming technical constraints affecting reproducibility.
PMID:42492028 | DOI:10.1200/PO-26-00207
