Mutations, Differential Gene Expression, and Chimeric Transcripts in Esophageal Squamous Cell Carcinoma Show High Heterogeneity

Abstract

Esophageal squamous cell carcinoma (ESCC) is a frequent and lethal neoplasia. As recent advances in targeted therapy have not improved ESCC prognosis, characterization of molecular alterations associated to this tumor is of foremost relevance. In this study, we analyze, for the first time, the complete genomic profile of ESCC by RNA-seq. TP53 was the most frequently mutated gene in the investigation and validation sets (78.6% and 67.4%, respectively). Differential expression analysis between tumor and nontumor adjacent mucosa showed 6698 differentially expressed genes, most of which were overexpressed (74%). Enrichment analysis identified overrepresentation of Wnt pathway, with overexpressed activators and underexpressed inactivators, suggesting activation of canonical and noncanonical Wnt signaling pathways. Higher WNT7B expression was associated with poor prognosis. Twenty-one gene fusions were identified in 50% of tumors, none of which involving the same genes in different patients; 71% of fusions involved syntenic genes. Comparisons with TCGA data showed co-amplification of seven gene pairs involved in fusions in the present study (~33%), suggesting that these rearrangements might have been driven by chromoanagenesis. In conclusion, genomic alterations in ESCC are highly heterogeneous, impacting negatively in target therapy development.

Drugging multiple same-allele driver mutations in cancer

“…Oncogenic mutations are commonly observed to be differentially expressed in tumors [11,12]. Although mostly unidentified (thus appearing rare), weak drivers are expected to be common.…”

A natural WNT signaling variant potently synergizes with Cdkn2ab loss in skin carcinogenesis

“…These ‘ in vivo ’ observations strongly support the stimulating effect of natural WNT7b overexpression on hfSCs and thereby its oncogenic role in the development TBCs. In addition, clinical data also implicate a contribution of subtle modulation of WNT7b expression to the development of oral and oesophageal squamous carcinoma 26,27 .…”

Upper Aerodigestive Tract Squamous Cell Carcinomas Show Distinct Overall DNA Methylation Profiles and Different Molecular Mechanisms behind WNT Signaling Disruption

“…Gene expression data from ESCC and LSCC cases was retrieved from previous work by the group [ 23 ]. Briefly, total RNA was isolated with the RNeasy Kit (Qiagen) and integrity was assessed with RNA 6000 Nano chip (Agilent, Santa Clara, CA, USA).…”

“…Nevertheless, few studies have compared global methylation profile of UADT tumor subsites, but did not investigate thoroughly subsite-specific alterations, particularly those affecting signaling pathways disruption such as the WNT pathway [ 14 , 18 , 19 ]. The WNT pathway plays a central role in development and stemness [ 20 , 21 , 22 ], and its dysregulation in epithelial tumors is recurrent [ 23 , 24 , 25 ]. Furthermore, WNT signaling pathway disruption was previously shown to impact on cancer patient prognosis and presents the potential of anti-cancer therapeutic approaches targeting this pathway [ 20 , 21 , 22 , 25 ].…”