Comprehensive Genomic Profiling of Anaplastic Thyroid Cancer Identifies Alterations in THRA, a Potential Modifier of Cellular Plasticity.

Lineage-specific cellular plasticity is one of the emerging hallmarks of cancer. The undifferentiated state of anaplastic thyroid cancer (ATC) represents an instance of cellular plasticity where lineage-specific molecular markers are underacknowledged. In this study, we identified recurrent mutations in the thyroid hormone receptor α (THRA) gene, which may play a role in lineage-specific cellular plasticity in ATC. We performed whole-exome sequencing and targeted sequencing of 68 formalin-fixed paraffin-embedded orphan tumors of ATC from Indian patients. Our analysis reveals the hallmark mutations in TP53 (approximately 42%), BRAF (approximately 10.3%), KRAS (approximately 2.9%), NRAS (29.4%), HRAS (23.5%), NF1 (1.5%), AKT1 (approximately 2.9%), and PIK3CA (approximately 1.5%) genes. Interestingly, we found significant mutations in THRA (approximately 11%) in our cohort, unlike the White population, which is a substantial gene in the thyroid cell's differentiation process. THRA mutations co-occur with TP53 and other hallmark genes, which suggests a synergetic molecular mechanism in phenotypic change in ATC. Our data reveal the significant association of THRA mutations potentially influencing cellular plasticity in a subset of patients with ATC.