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

Date Published: February 27, 2007

Publisher: Public Library of Science

Author(s): Patricia C Galipeau, Xiaohong Li, Patricia L Blount, Carlo C Maley, Carissa A Sanchez, Robert D Odze, Kamran Ayub, Peter S Rabinovitch, Thomas L Vaughan, Brian J Reid, Edison T Liu

Abstract: BackgroundSomatic 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 FindingsEsophageal 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).ConclusionsA 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.

Partial Text: Rapid advances in understanding the molecular pathogenesis of neoplasia have raised the possibility that molecular abnormalities may be used as “biomarkers” for cancer risk stratification and early detection as well as possible entry criteria for cancer-prevention trials [1–4]. Identification of inherited, highly penetrant mutations in some cancer-susceptibility genes is being incorporated into clinical practice as well as cancer-prevention strategies for patients with many familial cancer syndromes, including inherited breast cancer, hereditary nonpolyposis colon cancer, and adenomatous polyposis coli [5–10]. Although progress in developing predictive biomarkers from common somatic genetic abnormalities in at-risk tissues has been less striking, there is some evidence that this approach may be successful. Based on a genetic progression model for head and neck cancer [11,12], a series of retrospective, longitudinal studies have been performed on patients with the premalignant condition oral leukoplakia, resulting in potential biomarker panels for risk stratification [13–16]. Some of these biomarkers have been proposed as entry criteria for a randomized cancer-prevention trial using cyclo-oxygenase-2 and epidermal growth factor receptor inhibitors [4]. Understanding how modifiable exposures interact with the somatic genetic composition of a neoplasm will be important for individualized interventions and cancer prevention.

This investigation reports the results of a prospective cohort study of mechanistic-based genetic abnormalities evaluated as predictors of EA and demonstrates the modulating effect of NSAIDs on EA risk in patients with BE. We hypothesized that a panel of somatic genetic abnormalities involving TP53, CDKN2A, and DNA content could improve prediction of progression to EA and that NSAID use may modulate EA risk. In this longitudinal study spanning more than a decade, we showed that a combination of 17p LOH, 9p LOH, and DNA content tetraploidy and aneuploidy provide significant, independent EA risk prediction. NSAID use is associated with reduction of EA risk, and the protective effect was highly significant for patients who have multiple high-risk molecular abnormalities at baseline. These analyses include 34 EA endpoints, which is second only to our previous 15-y report of histology and flow cytometry (42 EAs) and substantially larger than most other longitudinal studies of biomarkers in BE from other centers, which have typically reported 12 or fewer incident cancers [41,42,68,69]. This prospective study has been conducted in a single center with a high-risk cohort; studies in other centers will be required to determine whether our results can be generalized to other patient populations and to validate the results for clinical application. Our results are consistent, however, with previous longitudinal studies of single biomarkers from other centers, including TP53 abnormalities and flow cytometry [41,42,70]. To our knowledge, no previous studies in patients with BE or any other human premalignant condition have prospectively evaluated the contributions of TP53 and CDKN2A gene inactivation (methylation, mutation, and LOH) and DNA content abnormalities in combination with candidate interventions to assess their potential utility as biomarkers for future cancer risk and cancer prevention.



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