Genetic Profiles of Aggressive Variants of Papillary Thyroid Carcinomas

SIMPLE SUMMARY: Aggressive variants of papillary thyroid carcinoma (PTC) are associated with unfavorable clinical outcomes. However, limited data exist on the genetic profile of these variants of PTC. We performed targeted next-generation sequencing in 36 tissue samples from patients with aggressive variants of PTC. Aggressive variants of PTC had a higher prevalence of the BRAF mutation and a lower prevalence of RAS mutation than other types of thyroid cancer. The prevalence of mutations in the TERT promoter, TP53, and genes encoding histone methyl transferases (HMTs), switch/sucrose non-fermenting (SWI/SNF) chromatin remodeling complex, and the phosphoinositide 3-kinase/protein kinase B (PKB/AKT)/mammalian target of the rapamycin (PI3K/AKT/mTOR) pathway was between the range of PTCs and poorly differentiated/anaplastic carcinoma from The Cancer Genome Atlas (TCGA) and the Memorial Sloan Kettering Cancer Center (MSKCC) data. ABSTRACT: Aggressive variants of papillary thyroid carcinoma (PTC) have been described with increasing frequency and are associated with unfavorable clinical outcomes. However, limited data exist on the comprehensive genetic profile of these variants. We performed targeted next-generation sequencing in 36 patients with aggressive variants of PTC and compared it to PTC from The Cancer Genome Atlas (TCGA) project and poorly differentiated thyroid cancers (PDTCs)/anaplastic thyroid cancers (ATCs) from the Memorial Sloan Kettering Cancer Center (MSKCC). BRAF mutation was the most prevalent (89%) in aggressive variants of PTC compared to that in other thyroid cancers. RAS mutation was identified in one patient (3%), which was less frequent than in others. TERT promoter mutation (17%) ranged between that of PTCs (9%) and PDTCs (40%). Tumor suppressor genes, ZFHX3, TP53, and CHEK2, were mutated in 14%, 3%, and 6% of aggressive variants of PTC, respectively. The mutation rate of TP53 (3%) was significantly higher than that of PTCs (0.7%) and lower than that of ATCs (73%). Mutations in three functional groups, histone methyl transferases, SWI/SNF chromatin remodeling complex, and the PI3K/AKT/mTOR pathway, were present in 11%, 14%, and 11% of samples, respectively. In conclusion, aggressive variants of PTC had higher BRAF and lower NRAS mutation prevalence than other thyroid cancers. The prevalence of mutations in the TERT promoter, TP53, and genes encoding three functional groups ranged between that of PTCs and PDTCs/ATCs.