NSAID use and somatic exomic mutations in Barrett’s esophagus
Abstract Background Use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) has been shown to protect against tetraploidy, aneuploidy, and chromosomal alterations in the metaplastic condition Barrett’s esophagus (BE) and to lower the incidence and mortality of esophageal adenocarcino...
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doaj-9f94c7d2b67e427691f7f022843a64f12020-11-25T00:01:32ZengBMCGenome Medicine1756-994X2018-02-0110111410.1186/s13073-018-0520-yNSAID use and somatic exomic mutations in Barrett’s esophagusPatricia C. Galipeau0Kenji M. Oman1Thomas G. Paulson2Carissa A. Sanchez3Qing Zhang4Jerry A. Marty5Jeffrey J. Delrow6Mary K. Kuhner7Thomas L. Vaughan8Brian J. Reid9Xiaohong Li10Division of Human Biology, Fred Hutchinson Cancer Research CenterDivision of Human Biology, Fred Hutchinson Cancer Research CenterDivision of Human Biology, Fred Hutchinson Cancer Research CenterDivision of Human Biology, Fred Hutchinson Cancer Research CenterBioinformatics Shared Resource, Fred Hutchinson Cancer Research CenterGenomics Shared Resource, Fred Hutchinson Cancer Research CenterGenomics and Bioinformatics Shared Resources, Fred Hutchinson Cancer Research CenterDepartment of Genome Sciences, University of Washington, Foege Building S-250Department of Epidemiology, University of Washington, Division of Public Health Sciences, Fred Hutchinson Cancer Research CenterDivision of Human Biology, Fred Hutchinson Cancer Research CenterDivision of Human Biology, Fred Hutchinson Cancer Research CenterAbstract Background Use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) has been shown to protect against tetraploidy, aneuploidy, and chromosomal alterations in the metaplastic condition Barrett’s esophagus (BE) and to lower the incidence and mortality of esophageal adenocarcinoma (EA). The esophagus is exposed to both intrinsic and extrinsic mutagens resulting from gastric reflux, chronic inflammation, and exposure to environmental carcinogens such as those found in cigarettes. Here we test the hypothesis that NSAID use inhibits accumulation of point mutations/indels during somatic genomic evolution in BE. Methods Whole exome sequences were generated from 82 purified epithelial biopsies and paired blood samples from a cross-sectional study of 41 NSAID users and 41 non-users matched by sex, age, smoking, and continuous time using or not using NSAIDs. Results NSAID use reduced overall frequency of point mutations across the spectrum of mutation types, lowered the frequency of mutations even when adjusted for both TP53 mutation and smoking status, and decreased the prevalence of clones with high variant allele frequency. Never smokers who consistently used NSAIDs had fewer point mutations in signature 17, which is commonly found in EA. NSAID users had, on average, a 50% reduction in functional gene mutations in nine cancer-associated pathways and also had less diversity in pathway mutational burden compared to non-users. Conclusions These results indicate NSAID use functions to limit overall mutations on which selection can act and supports a model in which specific mutant cell populations survive or expand better in the absence of NSAIDs.http://link.springer.com/article/10.1186/s13073-018-0520-yExome sequencingMutationApoptosisBarrett’s esophagusEsophageal adenocarcinomaAspirin |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Patricia C. Galipeau Kenji M. Oman Thomas G. Paulson Carissa A. Sanchez Qing Zhang Jerry A. Marty Jeffrey J. Delrow Mary K. Kuhner Thomas L. Vaughan Brian J. Reid Xiaohong Li |
spellingShingle |
Patricia C. Galipeau Kenji M. Oman Thomas G. Paulson Carissa A. Sanchez Qing Zhang Jerry A. Marty Jeffrey J. Delrow Mary K. Kuhner Thomas L. Vaughan Brian J. Reid Xiaohong Li NSAID use and somatic exomic mutations in Barrett’s esophagus Genome Medicine Exome sequencing Mutation Apoptosis Barrett’s esophagus Esophageal adenocarcinoma Aspirin |
author_facet |
Patricia C. Galipeau Kenji M. Oman Thomas G. Paulson Carissa A. Sanchez Qing Zhang Jerry A. Marty Jeffrey J. Delrow Mary K. Kuhner Thomas L. Vaughan Brian J. Reid Xiaohong Li |
author_sort |
Patricia C. Galipeau |
title |
NSAID use and somatic exomic mutations in Barrett’s esophagus |
title_short |
NSAID use and somatic exomic mutations in Barrett’s esophagus |
title_full |
NSAID use and somatic exomic mutations in Barrett’s esophagus |
title_fullStr |
NSAID use and somatic exomic mutations in Barrett’s esophagus |
title_full_unstemmed |
NSAID use and somatic exomic mutations in Barrett’s esophagus |
title_sort |
nsaid use and somatic exomic mutations in barrett’s esophagus |
publisher |
BMC |
series |
Genome Medicine |
issn |
1756-994X |
publishDate |
2018-02-01 |
description |
Abstract Background Use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) has been shown to protect against tetraploidy, aneuploidy, and chromosomal alterations in the metaplastic condition Barrett’s esophagus (BE) and to lower the incidence and mortality of esophageal adenocarcinoma (EA). The esophagus is exposed to both intrinsic and extrinsic mutagens resulting from gastric reflux, chronic inflammation, and exposure to environmental carcinogens such as those found in cigarettes. Here we test the hypothesis that NSAID use inhibits accumulation of point mutations/indels during somatic genomic evolution in BE. Methods Whole exome sequences were generated from 82 purified epithelial biopsies and paired blood samples from a cross-sectional study of 41 NSAID users and 41 non-users matched by sex, age, smoking, and continuous time using or not using NSAIDs. Results NSAID use reduced overall frequency of point mutations across the spectrum of mutation types, lowered the frequency of mutations even when adjusted for both TP53 mutation and smoking status, and decreased the prevalence of clones with high variant allele frequency. Never smokers who consistently used NSAIDs had fewer point mutations in signature 17, which is commonly found in EA. NSAID users had, on average, a 50% reduction in functional gene mutations in nine cancer-associated pathways and also had less diversity in pathway mutational burden compared to non-users. Conclusions These results indicate NSAID use functions to limit overall mutations on which selection can act and supports a model in which specific mutant cell populations survive or expand better in the absence of NSAIDs. |
topic |
Exome sequencing Mutation Apoptosis Barrett’s esophagus Esophageal adenocarcinoma Aspirin |
url |
http://link.springer.com/article/10.1186/s13073-018-0520-y |
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