SAT-567 Mutational Profile of Hurthle Cell Carcinomas: Recurrent Mutations in Wnt/β-catenin Pathway Genes

Abstract

Hürthle cell carcinomas (HCC) genomic characterization is evolving. Recent studies identified recurrent alterations in a few genes, chromosomal losses and mitochondrial DNA mutations. Gene expression studies demonstrated distinct profiles of PI3K-AKT-mTOR and Wnt/β-catenin pathways in widely invasive HCC. Potential driver mutations or mutations responsible for mitochondrion-rich phenotype are not completely defined. This study assessed HCC molecular profile using next-generation sequencing (NGS) of selected cancer-related genes and correlated with clinical characteristics and histological phenotypes. We evaluated 46 HCC and 8 adenomas (HCA) through a 97-gene NGS panel targeting MAPK, PI3K-AKT-mTOR, Wnt/β-catenin, Notch pathways, and other genes, such as TERT promoter and TP53. Variant callers Lofreq, Mutect and Lancet, identified somatic variants in matched carcinomas/normal thyroid, which were reviewed in Integrative Genomics Viewer. We searched genetic alterations in COSMIC70 database and predicted effects using in silico tools. Clinical and histological data were analyzed and compared to mutational profile. There were 46% of widely invasive HCC, 4.7% of which had lymph nodes and 9.5% distant metastases at diagnosis. On follow-up, 13% of patients had persistent/recurrent disease and 3% cancer-related deaths. Genetic alterations were identified in 54% of HCC, 221 single-nucleotide variants (SNV) and 6 insertions/deletions. Wnt/β-catenin pathway was most frequently involved (97 mutations in 41% HCC); FAT1 was the most recurrently mutated gene (31 mutations in 28% HCC), followed by APC (17 mutations in 15% HCC). Mutations in MAPK and mTOR pathways occurred in 30% and 22% of HCC, respectively. NRAS mutations were present in 3 HCC, so as 2 HCA. HRAS and KRAS mutations were found in one HCC each. There were 21 mutations described in COSMIC70, mostly in genes from Wnt and MAPK pathways: AKT2, APC, FGFR3, FLT3, GSK3B, HNF1A, IRS4, JAK2, KDR, KIT, KRAS, LRP6, MTOR, NOTCH2, NRAS and PIK3CG. Among remaining alterations, there were frameshift mutations in AGAP2, AXIN2 and FBXW7 genes, stop codons in ALK, CSNK1D, FAT1, NOTCH2 and TIMM 44, and 33 SNV predicted as deleterious. No BRAF or TP53 mutation was found, and there were 2 mutations in TERT promoter, different from C288T and C250T. We found no statistically significant association of clinical/histological features with mutational profile. In conclusion, HCC exhibited a wide range of mutations, mostly in Wnt/β-catenin pathway. FAT1, a tumor suppressor gene that controls mitochondrial activity to restrict cell growth, was the most frequently mutated gene, limited to HCC. Mutated FAT1 could activate Wnt/β-catenin pathway and provide growth advantage to mitochondrion-rich cells. We suppose FAT1 mutations are potential drivers and Wnt/β-catenin pathway plays a critical role in this distinct thyroid malignancy.