Abstract
e18142
Background: Follicular thyroid carcinoma (FTC), the second most common thyroid cancer, is diagnostically challenging due to overlapping features with benign adenomas, often requiring histologic review. While surgery and +/- adjuvant radioiodine ablation are standard therapy, radioiodine resistance underscores the need to define molecular drivers for targeted therapies. Using the AACR GENIE database, this study characterizes FTC’s mutational landscape to identify prognostic markers and therapeutic targets. Methods: The American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE)® database was accessed from cBioPortal (v16.1-public) on July 22, 2024 to identify all patients with FTC. The most common gene mutations, demographic correlations, and mutual exclusivities were analyzed using a two-sided T-test and non-parametric tests, with Benjamini-Hochberg False Discovery Rate (FDR) correction. Results: The cohort comprised 168 follicular thyroid cancer (FTC) samples from 161 patients. The patient population was predominantly female (n=101, 62.7%) and adult (n=149, 92.5%), with a smaller pediatric subset (n=18, 11.2%). By race, the cohort consisted primarily of White (n=107, 66.5%) and Black (n=13, 8.1%) patients, with the remaining patients (n=41, 25.4%) categorized as Asian, other, or unspecified. Samples were derived from primary (n=89, 55.3%) and metastatic (n=64, 39.8%) tumors. The most frequent mutations were observed in NRAS (33.9%, n=57), TERT (22.6%, n=38), DICER1 (15.5%, n=26), HRAS (11.9%, n=20), and PTEN (10.7%, n=18). Mutual exclusivity was found between NRAS and HRAS (p<0.001) and between NRAS and DICER1 (p=0.02). NRAS mutations were detected in 29.2% of primary tumors (n=26/89) and 42.2% of metastatic samples (n=27/64). DICER1 mutations were more prevalent in primary tumors (16.1%, n=10/62) compared to metastatic disease (2.0%, n=1/51; p<0.02). Mutations in BOD1L1 , UMODL1 , CDH23 , and NCOR2 were enriched in females (p<0.001). DICER1 mutations were more frequent in pediatric samples (44.4%, n=8/18) than in adult samples (4.6%, n=5/109; p<0.001), while TERT mutations were almost exclusively present in adults (p<0.001). NRAS was the most common mutation in adults (35.3%, n=53/150), whereas DICER1 was the most common in pediatric patients (44.4%, n=8/18). Conclusions: This study reveals NRAS and TERT as key drivers of FTC, with NRAS linked to metastatic progression and DICER1 enriched in pediatric and primary tumors. The mutual exclusivity of NRAS/HRAS and NRAS/DICER1 suggests divergent oncogenic pathways. Sex-specific mutations (e.g., BOD1L1 , NCOR2 ) and pediatric-adult disparities highlight the need for demographic-tailored therapies. These findings prioritize NRAS and TERT as targets for novel inhibitors or immunomodulators, particularly in radioiodine-resistant or metastatic FTC.