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.
Highlights
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 [1,2,3,4]
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; little is known about the ability of a biomarker panel to predict progression to cancer nor how NSAID use may modulate progression
NSAIDs are associated with reduced EA risk, especially in patients with multiple high-risk molecular abnormalities
Summary
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 [1,2,3,4]. 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 [13,14,15,16] 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]. Scientists have identified numerous genetic changes that occur in tumors and are investigating whether these molecular abnormalities can be used as ‘‘biomarkers’’ to choose the best treatments for patients, to identify who will benefit from cancerprevention strategies, to detect cancer early, and to predict which cancers are most likely to become life-threatening This last application is important for cancers with a well-defined premalignant stage. People with Barrett’s esophagus are much more likely to develop esophageal cancer than the general population
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
