Impact of mutations in Toll-like receptor pathway genes on esophageal carcinogenesis.
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 prom...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2017-05-01
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| Series: | PLoS Genetics |
| Online Access: | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1006808&type=printable |
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| author | Daffolyn Rachael Fels Elliott Juliane Perner Xiaodun Li Martyn F Symmons Brett Verstak Matthew Eldridge Lawrence Bower Maria O'Donovan Nick J Gay OCCAMS Consortium Rebecca C Fitzgerald |
| author_facet | Daffolyn Rachael Fels Elliott Juliane Perner Xiaodun Li Martyn F Symmons Brett Verstak Matthew Eldridge Lawrence Bower Maria O'Donovan Nick J Gay OCCAMS Consortium Rebecca C Fitzgerald |
| author_sort | Daffolyn Rachael Fels Elliott |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-795eeb65e0a5409c98148b4a71db3485 |
| institution | Kabale University |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2017-05-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj-art-795eeb65e0a5409c98148b4a71db34852025-08-20T03:24:29ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042017-05-01135e100680810.1371/journal.pgen.1006808Impact of mutations in Toll-like receptor pathway genes on esophageal carcinogenesis.Daffolyn Rachael Fels ElliottJuliane PernerXiaodun LiMartyn F SymmonsBrett VerstakMatthew EldridgeLawrence BowerMaria O'DonovanNick J GayOCCAMS ConsortiumRebecca C FitzgeraldEsophageal 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.https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1006808&type=printable |
| spellingShingle | Daffolyn Rachael Fels Elliott Juliane Perner Xiaodun Li Martyn F Symmons Brett Verstak Matthew Eldridge Lawrence Bower Maria O'Donovan Nick J Gay OCCAMS Consortium Rebecca C Fitzgerald Impact of mutations in Toll-like receptor pathway genes on esophageal carcinogenesis. PLoS Genetics |
| title | Impact of mutations in Toll-like receptor pathway genes on esophageal carcinogenesis. |
| title_full | Impact of mutations in Toll-like receptor pathway genes on esophageal carcinogenesis. |
| title_fullStr | Impact of mutations in Toll-like receptor pathway genes on esophageal carcinogenesis. |
| title_full_unstemmed | Impact of mutations in Toll-like receptor pathway genes on esophageal carcinogenesis. |
| title_short | Impact of mutations in Toll-like receptor pathway genes on esophageal carcinogenesis. |
| title_sort | impact of mutations in toll like receptor pathway genes on esophageal carcinogenesis |
| url | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1006808&type=printable |
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