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NSAIDS and Somatic 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 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 nonusers 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 nonusers. 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. Galipeau PC, et al. Genome Med. 2018 Feb 27;10(1):17. PMID: 29486792.

PROVIDER: phs001654 | dbGaP |

REPOSITORIES: dbGaP

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			Action	DRS
	GapExchange_phs001654.v1.p1.xml	Xml
	dbGaPEx2.1.5.xsd	Other
	Study_Report.phs001654.AspirinInflammation.v1.p1.MULTI.pdf	Pdf
	manifest_phs001654.AspirinInflammation.v1.p1.c1.DS-BE.pdf	Pdf
	datadict_v2.xsl	Other

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Project description:INTRODUCTION: CDKN2A (p16) inactivation is common in lung cancer and occurs via homozygous deletions, methylation of promoter region, or point mutations. Although p16 promoter methylation has been linked to KRAS mutation and smoking, the associations between p16 inactivation mechanisms and other common genetic mutations and smoking status are still controversial or unknown. METHODS: We determined all three p16 inactivation mechanisms with the use of multiple methodologies for genomic status, methylation, RNA, and protein expression, and correlated them with EGFR, KRAS, STK11 mutations and smoking status in 40 cell lines and 45 tumor samples of primary non-small-cell lung carcinoma. We also performed meta-analyses to investigate the impact of smoke exposure on p16 inactivation. RESULTS: p16 inactivation was the major mechanism of RB pathway perturbation in non-small-cell lung carcinoma, with homozygous deletion being the most frequent method, followed by methylation and the rarer point mutations. Inactivating mechanisms were tightly correlated with loss of mRNA and protein expression. p16 inactivation occurred at comparable frequencies regardless of mutational status of EGFR, KRAS, and STK11, however, the major inactivation mechanism of p16 varied. p16 methylation was linked to KRAS mutation but was mutually exclusive with EGFR mutation. Cell lines and tumor samples demonstrated similar results. Our meta-analyses confirmed a modest positive association between p16 promoter methylation and smoking. CONCLUSION: Our results confirm that all the inactivation mechanisms are truly associated with loss of gene product and identify specific associations between p16 inactivation mechanisms and other genetic changes and smoking status. 40 NSCLC cell lines were profiled on Illumina WG6-V3 expression arrays. They consist of 4 groups of 10 cell lines each: non-smokers with EGFR mutation, non-smokers with EGFR wild-type, smokers with KRAS mutation, smokers with KRAS wild-type. Note that smoking status is not always clear.

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NSAIDS and Somatic Mutations in Barrett's Esophagus

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