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.

Methods and findings: 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.

Figure 1. Modulation of EA Risk by NSAIDs in Participants with Different Baseline Abnormalities

Two hundred and forty-one patients are classified according to whether they have (A) baseline 17p LOH (n = 46), (B) baseline DNA content abnormalities (aneuploidy and/or tetraploidy) (n = 41), (C) baseline 9p LOH (n = 144), or (D) more than one baseline abnormality (top two curves) or one or less abnormality (lower two curves). Shown are Kaplan-Meier curves of cancer incidence rates in patients who are NSAID nonusers (former or never users, red curves) or NSAID users (current or user during follow-up, black curves).

Figure 2. Cumulative EA Incidence with Combinations of Abnormalities (17p LOH, DNA Content Abnormality, 9p LOH) in NSAID Nonusers and NSAID Users

Cancer incidence rates are shown for participants with no selected abnormalities (17p LOH, DNA content abnormalities [aneuploidy and/or tetraploidy], or 9p LOH) at baseline (red), any one abnormality (green), any combination of two abnormalities (blue), or all three abnormalities (black). (A) All participants. When comparing NSAID nonusers (B) and NSAID users (C) there is a strong significant trend toward EA risk reduction in the NSAID users group for all abnormality combinations (Mantel-Haenszel test p = 0.01).