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Impact of mutations in Toll-like receptor pathway genes on esophageal carcinogenesis.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Fels Elliott, Daffolyn Rachael 
Perner, Juliane 
Li, Xiaodun 
Symmons, Martyn F 
Verstak, Brett 

Abstract

Esophageal adenocarcinoma (EAC) develops in an inflammatory microenvironment with reduced microbial diversity, but mechanisms for these influences remain poorly characterized. We hypothesized that mutations targeting the Toll-like receptor (TLR) pathway could disrupt innate immune signaling and promote a microenvironment that favors tumorigenesis. Through interrogating whole genome sequencing data from 171 EAC patients, we showed that non-synonymous mutations collectively affect the TLR pathway in 25/171 (14.6%, PathScan p = 8.7x10-5) tumors. TLR mutant cases were associated with more proximal tumors and metastatic disease, indicating possible clinical significance of these mutations. Only rare mutations were identified in adjacent Barrett's esophagus samples. We validated our findings in an external EAC dataset with non-synonymous TLR pathway mutations in 33/149 (22.1%, PathScan p = 0.05) tumors, and in other solid tumor types exposed to microbiomes in the COSMIC database (10,318 samples), including uterine endometrioid carcinoma (188/320, 58.8%), cutaneous melanoma (377/988, 38.2%), colorectal adenocarcinoma (402/1519, 26.5%), and stomach adenocarcinoma (151/579, 26.1%). TLR4 was the most frequently mutated gene with eleven mutations in 10/171 (5.8%) of EAC tumors. The TLR4 mutants E439G, S570I, F703C and R787H were confirmed to have impaired reactivity to bacterial lipopolysaccharide with marked reductions in signaling by luciferase reporter assays. Overall, our findings show that TLR pathway genes are recurrently mutated in EAC, and TLR4 mutations have decreased responsiveness to bacterial lipopolysaccharide and may play a role in disease pathogenesis in a subset of patients.

Description

Keywords

Adenocarcinoma, Aged, Carcinogenesis, Cell Line, Tumor, Esophageal Neoplasms, Female, HEK293 Cells, Humans, Lipopolysaccharides, Male, Middle Aged, Mutation, Protein Binding, Toll-Like Receptor 4

Journal Title

PLoS Genet

Conference Name

Journal ISSN

1553-7390
1553-7404

Volume Title

13

Publisher

Public Library of Science (PLoS)
Sponsorship
Cancer Research Uk (None)
Wellcome Trust (100321/Z/12/Z)
Cancer Research UK (20406)