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

PLoS Genetics
Daffolyn Rachael Fels ElliottRebecca C Fitzgerald

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 m...Continue Reading

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Citations

Jun 5, 2019·The Kaohsiung Journal of Medical Sciences·Ai-Guo MaQing Wang
Oct 28, 2019·Oncoimmunology·Tong LiElke Burgermeister
Jan 5, 2018·Expert Opinion on Biological Therapy·Isabel AndiaNicola Maffulli
Apr 22, 2020·Cell Death & Disease·Xiu-Qiong FuZhi-Ling Yu

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Methods Mentioned

BETA
exome sequencing
PCR
confocal microscopy
transfection
ELISA
RNA-Seq
amplicon sequencing
reverse transcription PCR

Software Mentioned

Mathematica
UCSF Chimera
PathSeq
PolyPhen
R
PathScan
Manta
COOT ( Crystallographic Object - Oriented Toolkit )
Graphpad Prism
GATK

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