Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 4 (2), e67

NSAIDs Modulate CDKN2A, TP53, and DNA Content Risk for Progression to Esophageal Adenocarcinoma

Affiliations

NSAIDs Modulate CDKN2A, TP53, and DNA Content Risk for Progression to Esophageal Adenocarcinoma

Patricia C Galipeau et al. PLoS Med.

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.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
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
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).

Similar articles

See all similar articles

Cited by 108 PubMed Central articles

See all "Cited by" articles

References

    1. O'Shaughnessy JA, Kelloff GJ, Gordon GB, Dannenberg AJ, Hong WK, et al. Treatment and prevention of intraepithelial neoplasia: An important target for accelerated new agent development. Clin Cancer Res. 2002;8:314–346. - PubMed
    1. Kelloff GJ, O'Shaughnessy JA, Gordon GB, Hawk ET, Sigman CC. Counterpoint: Because some surrogate end point biomarkers measure the neoplastic process they will have high utility in the development of cancer chemopreventive agents against sporadic cancers. Cancer Epidemiol Biomarkers Prev. 2003;12:593–596. - PubMed
    1. Sullivan Pepe M, Etzioni R, Feng Z, Potter JD, Thompson ML, et al. Phases of biomarker development for early detection of cancer. J Natl Cancer Inst. 2001;93:1054–1061. - PubMed
    1. Dannenberg AJ, Lippman SM, Mann JR, Subbaramaiah K, DuBois RN. Cyclooxygenase-2 and epidermal growth factor receptor: Pharmacologic targets for chemoprevention. J Clin Oncol. 2005;23:254–266. - PubMed
    1. King MC, Marks JH, Mandell JB. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science. 2003;302:643–646. - PubMed

Publication types

MeSH terms

Substances

Feedback