NSAIDs modulate CDKN2A, TP53, and DNA content risk for progression to esophageal adenocarcinoma

Patricia C. Galipeau, Xiaohong Li, Patricia L. Blount, Carlo Maley, Carissa A. Sanchez, Robert D. Odze, Kamran Ayub, Peter S. Rabinovitch, Thomas L. Vaughan, Brian J. Reid

Research output: Contribution to journalArticle

182 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)342-353
Number of pages12
JournalPLoS Medicine
Volume4
Issue number2
DOIs
StatePublished - Feb 2007
Externally publishedYes

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Loss of Heterozygosity
Adenocarcinoma
Anti-Inflammatory Agents
DNA
Pharmaceutical Preparations
Barrett Esophagus
Tetraploidy
Aneuploidy
Confidence Intervals
Drug Users
Methylation
Multiple Abnormalities
Aptitude
Incidence
Risk Reduction Behavior
Aspirin
Neoplasms
Flow Cytometry
Cohort Studies
Biomarkers

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Galipeau, P. C., Li, X., Blount, P. L., Maley, C., Sanchez, C. A., Odze, R. D., ... Reid, B. J. (2007). NSAIDs modulate CDKN2A, TP53, and DNA content risk for progression to esophageal adenocarcinoma. PLoS Medicine, 4(2), 342-353. https://doi.org/10.1371/journal.pmed.0040067

NSAIDs modulate CDKN2A, TP53, and DNA content risk for progression to esophageal adenocarcinoma. / Galipeau, Patricia C.; Li, Xiaohong; Blount, Patricia L.; Maley, Carlo; Sanchez, Carissa A.; Odze, Robert D.; Ayub, Kamran; Rabinovitch, Peter S.; Vaughan, Thomas L.; Reid, Brian J.

In: PLoS Medicine, Vol. 4, No. 2, 02.2007, p. 342-353.

Research output: Contribution to journalArticle

Galipeau, PC, Li, X, Blount, PL, Maley, C, Sanchez, CA, Odze, RD, Ayub, K, Rabinovitch, PS, Vaughan, TL & Reid, BJ 2007, 'NSAIDs modulate CDKN2A, TP53, and DNA content risk for progression to esophageal adenocarcinoma', PLoS Medicine, vol. 4, no. 2, pp. 342-353. https://doi.org/10.1371/journal.pmed.0040067
Galipeau, Patricia C. ; Li, Xiaohong ; Blount, Patricia L. ; Maley, Carlo ; Sanchez, Carissa A. ; Odze, Robert D. ; Ayub, Kamran ; Rabinovitch, Peter S. ; Vaughan, Thomas L. ; Reid, Brian J. / NSAIDs modulate CDKN2A, TP53, and DNA content risk for progression to esophageal adenocarcinoma. In: PLoS Medicine. 2007 ; Vol. 4, No. 2. pp. 342-353.
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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.",
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AU - Galipeau, Patricia C.

AU - Li, Xiaohong

AU - Blount, Patricia L.

AU - Maley, Carlo

AU - Sanchez, Carissa A.

AU - Odze, Robert D.

AU - Ayub, Kamran

AU - Rabinovitch, Peter S.

AU - Vaughan, Thomas L.

AU - Reid, Brian J.

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Y1 - 2007/2

N2 - 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.

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