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

Galipeau PC, Li X, Blount PL, Maley CC, Sanchez CA, Odze RD, Ayub K, Rabinovitch PS, Vaughan TL, Reid BJ - PLoS Med. (2007)

Bottom Line: 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).NSAIDs are associated with reduced EA risk, especially in patients with multiple high-risk molecular abnormalities.

View Article: PubMed Central - PubMed

Affiliation: Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America. pgal@fhcrc.org

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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Related in: MedlinePlus

Modulation of EA Risk by NSAIDs in Participants with Different Baseline AbnormalitiesTwo 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).
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pmed-0040067-g001: Modulation of EA Risk by NSAIDs in Participants with Different Baseline AbnormalitiesTwo 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).

Mentions: We sought to evaluate the extent to which specific tissue-based, mechanistically derived molecular markers, both alone and in combination, predict risk of progression to EA in patients with BE. The analytic approach is summarized as follows. (1) Univariate Cox proportional hazard analyses (not adjusted for host variables or other markers) were used to determine the EA risk of patients with each marker, measured at baseline at 2-, 6-, and 10-y follow-up time points (Table 2). (2) Stepwise multivariate Cox regression was used to select, from among all of the available molecular markers, a subset which independently contributes to EA risk prediction (Table 3). (3) Cumulative EA incidence and relative risk (RR) of progression to EA at 10 y were calculated for patients with different numbers of the selected markers at baseline relative to patients with no abnormalities (Table 4). To determine the contribution of known or suspected nongenetic host factors to EA risk prediction, we incorporated these host factors together with all molecular markers in a multivariate Cox model. Only NSAID use showed significant independent prediction in combination with molecular markers in this multivariate model. The predictive ability of the selected molecular markers was evaluated among NSAID users and nonusers (Figures 1 and 2).


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

Galipeau PC, Li X, Blount PL, Maley CC, Sanchez CA, Odze RD, Ayub K, Rabinovitch PS, Vaughan TL, Reid BJ - PLoS Med. (2007)

Modulation of EA Risk by NSAIDs in Participants with Different Baseline AbnormalitiesTwo 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).
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC1808095&req=5

pmed-0040067-g001: Modulation of EA Risk by NSAIDs in Participants with Different Baseline AbnormalitiesTwo 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).
Mentions: We sought to evaluate the extent to which specific tissue-based, mechanistically derived molecular markers, both alone and in combination, predict risk of progression to EA in patients with BE. The analytic approach is summarized as follows. (1) Univariate Cox proportional hazard analyses (not adjusted for host variables or other markers) were used to determine the EA risk of patients with each marker, measured at baseline at 2-, 6-, and 10-y follow-up time points (Table 2). (2) Stepwise multivariate Cox regression was used to select, from among all of the available molecular markers, a subset which independently contributes to EA risk prediction (Table 3). (3) Cumulative EA incidence and relative risk (RR) of progression to EA at 10 y were calculated for patients with different numbers of the selected markers at baseline relative to patients with no abnormalities (Table 4). To determine the contribution of known or suspected nongenetic host factors to EA risk prediction, we incorporated these host factors together with all molecular markers in a multivariate Cox model. Only NSAID use showed significant independent prediction in combination with molecular markers in this multivariate model. The predictive ability of the selected molecular markers was evaluated among NSAID users and nonusers (Figures 1 and 2).

Bottom Line: 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).NSAIDs are associated with reduced EA risk, especially in patients with multiple high-risk molecular abnormalities.

View Article: PubMed Central - PubMed

Affiliation: Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America. pgal@fhcrc.org

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.

Show MeSH
Related in: MedlinePlus