Genomic Characterization of Oncocytic Carcinoma of the Thyroid Using a Large Multi-Institutional Database

Characterize the somatic mutations in Oncocytic Carcinoma of the Thyroid (OCA) using a large, multi-institutional database to identify potential therapeutic targets and gain insights into tumor biology.

Cross-sectional study.

Retrospective nationwide database review.

Genomic data from 130 OCA samples, representing 124 adult patients, were retrieved from the American Association for Cancer Research (AACR) Project Genomics, Evidence, and Neoplasia Information Exchange (GENIE) database (v17.0-public). Analysis focused on nonsynonymous somatic mutations identified via whole-genome, whole-exome, or targeted panel sequencing after standardized filtering. Mutation frequencies, enrichment based on gender and metastatic status (primary vs. metastatic), and patterns of co-occurrence or mutual exclusivity were statistically evaluated.

The most frequently mutated genes were TERT (33.1%, predominantly promoter mutations), TP53 (20.0%), DAXX (16.2%), KMT2D (13.1%), NF1 (12.3%), and PTEN (10.0%). Significant gender-specific enrichment was identified, notably MST1R mutations exclusive to females (10.7%) and PRKDC mutations exclusive to males (16.7%). Mutations in PC, PCLO, MEN1, and TSC2 were significantly enriched in metastatic samples. DAXX and CDKN1A mutations exhibited significant co-occurrence, whereas TERT mutations were mutually exclusive with DAXX alterations.

The genomic landscape of OCA is marked by frequent TERT promoter mutations and distinct mutational patterns associated with patient gender and tumor metastatic status. These findings highlight potential molecular subtypes, reveal pathways potentially driving metastasis (eg, involving MEN1/TSC2), and identify novel sex-specific alterations (MST1R, PRKDC), offering avenues for improved development of targeted therapeutic strategies for OCA.