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

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.
PMID
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Authors

Mayor MeshTerms
Keywords
Journal Title plos genetics
Publication Year Start




PMID- 28531216
OWN - NLM
STAT- Publisher
DA  - 20170522
LR  - 20170522
IS  - 1553-7404 (Electronic)
IS  - 1553-7390 (Linking)
VI  - 13
IP  - 5
DP  - 2017 May 22
TI  - Impact of mutations in Toll-like receptor pathway genes on esophageal
      carcinogenesis.
PG  - e1006808
LID - 10.1371/journal.pgen.1006808 [doi]
AB  - 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.
FAU - Fels Elliott, Daffolyn Rachael
AU  - Fels Elliott DR
AD  - MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge,
      Cambridge, United Kingdom.
FAU - Perner, Juliane
AU  - Perner J
AD  - Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge,
      United Kingdom.
FAU - Li, Xiaodun
AU  - Li X
AD  - MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge,
      Cambridge, United Kingdom.
FAU - Symmons, Martyn F
AU  - Symmons MF
AD  - Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
FAU - Verstak, Brett
AU  - Verstak B
AD  - Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
FAU - Eldridge, Matthew
AU  - Eldridge M
AUID- ORCID: http://orcid.org/0000-0002-5799-8911
AD  - Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge,
      United Kingdom.
FAU - Bower, Lawrence
AU  - Bower L
AD  - Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge,
      United Kingdom.
FAU - O'Donovan, Maria
AU  - O'Donovan M
AD  - Department of Histopathology, Cambridge University Hospital NHS Trust, Cambridge,
      United Kingdom.
FAU - Gay, Nick J
AU  - Gay NJ
AUID- ORCID: http://orcid.org/0000-0002-2782-7169
AD  - Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
CN  - OCCAMS Consortium
FAU - Fitzgerald, Rebecca C
AU  - Fitzgerald RC
AD  - MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge,
      Cambridge, United Kingdom.
LA  - eng
PT  - Journal Article
DEP - 20170522
PL  - United States
TA  - PLoS Genet
JT  - PLoS genetics
JID - 101239074
EDAT- 2017/05/23 06:00
MHDA- 2017/05/23 06:00
CRDT- 2017/05/23 06:00
PHST- 2017/02/01 [received]
PHST- 2017/05/09 [accepted]
AID - 10.1371/journal.pgen.1006808 [doi]
AID - PGENETICS-D-17-00227 [pii]
PST - aheadofprint
SO  - PLoS Genet. 2017 May 22;13(5):e1006808. doi: 10.1371/journal.pgen.1006808.

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