title: NSAIDs modulate CDKN2A, TP53, and DNA content risk for progression to esophageal adenocarcinoma.
abstract: BACKGROUND
  Somatic genetic CDKN2A, TP53, and DNA content abnormalities are common in many human cancers and their precursors, including esophageal adenocarcinoma (EA) and Barrett's esophagus (BE), conditions for which aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) have been proposed as possible chemopreventive agents; however, little is known about the ability of a biomarker panel to predict progression to cancer nor how NSAID use may modulate progression. We aimed to evaluate somatic genetic abnormalities with NSAIDs as predictors of EA in a prospective cohort study of patients with BE.
  
  
  RESULTS
  Esophageal biopsies from 243 patients with BE were evaluated at baseline for TP53 and CDKN2A (p16) alterations, tetraploidy, and aneuploidy using sequencing; loss of heterozygosity (LOH); methylation-specific PCR; and flow cytometry. At 10 y, all abnormalities, except CDKN2A mutation and methylation, contributed to EA risk significantly by univariate analysis, ranging from 17p LOH (relative risk [RR] = 10.6; 95% confidence interval [CI] 5.2-21.3, p < 0.001) to 9p LOH (RR = 2.6; 95% CI 1.1-6.0, p = 0.03). A panel of abnormalities including 17p LOH, DNA content tetraploidy and aneuploidy, and 9p LOH was the best predictor of EA (RR = 38.7; 95% CI 10.8-138.5, p < 0.001). Patients with no baseline abnormality had a 12% 10-y cumulative EA incidence, whereas patients with 17p LOH, DNA content abnormalities, and 9p LOH had at least a 79.1% 10-y EA incidence. In patients with zero, one, two, or three baseline panel abnormalities, there was a significant trend toward EA risk reduction among NSAID users compared to nonusers (p = 0.01). The strongest protective effect was seen in participants with multiple genetic abnormalities, with NSAID nonusers having an observed 10-y EA risk of 79%, compared to 30% for NSAID users (p < 0.001).
  
  
  CONCLUSIONS
  A combination of 17p LOH, 9p LOH, and DNA content abnormalities provided better EA risk prediction than any single TP53, CDKN2A, or DNA content lesion alone. NSAIDs are associated with reduced EA risk, especially in patients with multiple high-risk molecular abnormalities.
authors.affiliation: Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America. pgal@fhcrc.org
authors.forename: Patricia C
authors.initials: PC
authors.lastname: Galipeau
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Li
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Blount
authors.forename: Carlo C
authors.initials: CC
authors.lastname: Maley
authors.forename: Carissa A
authors.initials: CA
authors.lastname: Sanchez
authors.forename: Robert D
authors.initials: RD
authors.lastname: Odze
authors.forename: Kamran
authors.initials: K
authors.lastname: Ayub
authors.forename: Peter S
authors.initials: PS
authors.lastname: Rabinovitch
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Vaughan
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Reid
mesh_terms: D000230:Adenocarcinoma / Q000453:epidemiology / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000782:Aneuploidy; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001471:Barrett Esophagus / Q000473:pathology; D001706:Biopsy; D002886:Chromosomes, Human, Pair 17; D002899:Chromosomes, Human, Pair 9; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D004247:DNA / Q000235:genetics*; D019175:DNA Methylation; D004938:Esophageal Neoplasms / Q000453:epidemiology / Q000235:genetics*; D004945:Esophagoscopy; D004947:Esophagus / Q000473:pathology; D005260:Female; D006801:Humans; D015994:Incidence; D008137:Longitudinal Studies; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011446:Prospective Studies; D018570:Risk Assessment; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016159:Tumor Suppressor Protein p53; D004247:DNA