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

Abstract

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.

A clinical and molecular pathology prediction model for central lymph node metastasis in cN0 papillary thyroid microcarcinoma

“…The second most frequent mutation is a RAS mutation in preoperative thyroid FNA. RAS mutations include 3 subtypes: HRAS, KRAS, and NRAS, the most common of which is NRAS ( 45 ). RAS mutations promote invasion mainly in follicular tumors, relate to local lymph node metastasis and distant metastasis ( 46 ).…”

Fine-needle biopsy of thyroid nodules and the contribution of molecular analysis of BRAF and RAS mutations

“…Determining RAS mutations remains controversial, as in the population of individuals with this mutation, it is often associated with benign follicular lesions such as benign adenoma. On the other hand, some studies have pointed to the role of RAS mutation in the process of tumorigenesis and as an early transformational event associated with the transition from adenoma to carcinoma -the so-called histological continuum from benign to malignant lesions (16,17). The positivity of RAS mutations plays benefi cial role in the presence of mutations of other oncogenes when it increases the risk of tumor aggressiveness.…”

Molecular Signature Expands the Landscape of Driver Negative Thyroid Cancers

“…RNA isolation and library preparation were conducted as previously described [18] using TrueSeq Stranded mRNA sample preparation kit v.2 (Illumina Inc., San Diego, CA, USA) on an Illumina NextSeq 500 sequencing platform (Illumina Inc.) at the Centro de Oncologia Molecular, Hospital Sírio-libanês, São Paulo, Brazil (Table S1).…”

“…A pipeline was developed for detection of single nucleotide variants (SNVs) and small insertions/deletions (InDels) from RNA-sequencing data. SNVs and InDels were called using the Genomic Analysis Toolkit (GATK) HaplotyperCaller version 3.7.0, as previously described [18].…”