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

Abstract

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 (<i>THRA</i>) 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 <i>TP53</i> (approximately 42%), <i>BRAF</i> (approximately 10.3%), <i>KRAS</i> (approximately 2.9%), <i>NRAS</i> (29.4%), <i>HRAS</i> (23.5%), <i>NF1</i> (1.5%), <i>AKT1</i> (approximately 2.9%), and <i>PIK3CA</i> (approximately 1.5%) genes. Interestingly, we found significant mutations in <i>THRA</i> (approximately 11%) in our cohort, unlike the White population, which is a substantial gene in the thyroid cell's differentiation process. <i>THRA</i> 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 <i>THRA</i> mutations potentially influencing cellular plasticity in a subset of patients with ATC.