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Genome Med. 2018 Feb 27;10(1):17. doi: 10.1186/s13073-018-0520-y.

NSAID use and somatic exomic mutations in Barrett's esophagus.

Author information

1
Division of Human Biology, Fred Hutchinson Cancer Research Center, PO Box 19024, 1100 Fairview Ave N, Seattle, WA, 98109-1024, USA.
2
Bioinformatics Shared Resource, Fred Hutchinson Cancer Research Center, PO Box 19024, Seattle, WA, 98109-1024, USA.
3
Genomics Shared Resource, Fred Hutchinson Cancer Research Center, PO Box 19024, Seattle, WA, 98109-1024, USA.
4
Genomics and Bioinformatics Shared Resources, Fred Hutchinson Cancer Research Center, PO Box 19024, Seattle, WA, 98109-1024, USA.
5
Department of Genome Sciences, University of Washington, Foege Building S-250, Box 355065, 3720 15th Ave NE, Seattle, WA, 98195-5065, USA.
6
Department of Epidemiology, University of Washington, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, PO Box 19024, Seattle, WA, 98109-1024, USA.
7
Department of Medicine, University of Washington, Division of Human Biology, Fred Hutchinson Cancer Research Center, PO Box 19024, Seattle, WA, 98109-1024, USA.
8
Division of Human Biology, Fred Hutchinson Cancer Research Center, PO Box 19024, 1100 Fairview Ave N, Seattle, WA, 98109-1024, USA. xili@fredhutch.org.

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.

KEYWORDS:

Apoptosis; Aspirin; Barrett’s esophagus; Cancer prevention; Esophageal adenocarcinoma; Exome sequencing; Mutation; NSAID; TP53; Tobacco smoking

PMID:
29486792
PMCID:
PMC5830331
DOI:
10.1186/s13073-018-0520-y
[Indexed for MEDLINE]
Free PMC Article

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