Evidence of Cooperation between Hippo Pathway and RAS Mutation in Thyroid Carcinomas.

Abstract

Simple SummaryRAS mutations have been reported in a wide range of thyroid cancer histological types, from benign to aggressive phenotypes. The presence of RAS mutations in benign lesions suggests that the mutation alone is unlikely to lead to a malignant transformation per se, and thus, additional aberrations are necessary for this transformation. In this study, we initially screened a cohort of 120 thyroid carcinomas with a panel of known driver mutations and identified 11 RAS-mutated samples. An RNA-Seq analysis of those 11 RAS-positive samples identified that the Hippo pathway was both mutated and differentially expressed in the RAS-positive tumors. The gene expression analysis of 60 RAS-positive The Cancer Genome Atlas (TCGA) papillary thyroid carcinomas (PTC) samples supported our findings. Thyroid cancer incidences have been steadily increasing worldwide and are projected to become the fourth leading cancer diagnosis by 2030. Improved diagnosis and prognosis predictions for this type of cancer depend on understanding its genetic bases and disease biology. RAS mutations have been found in a wide range of thyroid tumors, from benign to aggressive thyroid carcinomas. Based on that and in vivo studies, it has been suggested that RAS cooperates with other driver mutations to induce tumorigenesis. This study aims to identify genetic alterations or pathways that cooperate with the RAS mutation in the pathogenesis of thyroid cancer. From a cohort of 120 thyroid carcinomas, 11 RAS-mutated samples were identified. The samples were subjected to RNA-Sequencing analyses. The mutation analysis in our eleven RAS-positive cases uncovered that four genes that belong to the Hippo pathway were mutated. The gene expression analysis revealed that this pathway was dysregulated in the RAS-positive samples. We additionally explored the mutational status and expression profiling of 60 RAS-positive papillary thyroid carcinomas (PTC) from The Cancer Genome Atlas (TCGA) cohort. Altogether, the mutational landscape and pathway enrichment analysis (gene set enrichment analysis (GSEA) and Kyoto Encyclopedia of Genes and Genome (KEGG)) detected the Hippo pathway as dysregulated in RAS-positive thyroid carcinomas. Finally, we suggest a crosstalk between the Hippo and other signaling pathways, such as Wnt and BMP.