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

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          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).


          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.


          In a ten-year study of people with Barrett's esophagus, nonsteroidal anti-inflamatory drugs were associated with reduced risk of esophageal adenocarcinoma, especially in patients with multiple high-risk molecular abnormalities.

          Editors' Summary


          Normally, the cells in the human body divide only when extra cells are needed, after an injury, for example. Sometimes, however, cells accumulate genetic changes (mutations) that allow them to divide uncontrollably to form a disorganized mass or tumor. If these altered cells also acquire mutations that allow them to spread around the body, a malignant tumor or cancer results. Scientists have identified numerous genetic changes that occur in tumors and are now investigating whether these molecular abnormalities can be used as “biomarkers” to choose the best treatments for patients, to identify who will benefit from cancer-prevention strategies, to detect cancer early, and to predict which cancers are most likely to become life-threatening. This last application is particularly important for cancers with a well-defined premalignant stage. Because the cells in premalignant tissues have acquired some of the genetic changes required for cancer development, they are more likely to become malignant than normal cells. Barrett's esophagus, for example, is a premalignant disorder of the muscular tube that takes food from the mouth to the stomach. People with Barrett's esophagus are much more likely to develop esophageal cancer than the general population.

          Why Was This Study Done?

          Esophageal cancer is often incurable by the time it is detected, so it would be helpful to know which people with Barrett's esophagus are most likely to develop esophageal cancer—only 1 in 200 of them develop cancer each year. In this study, the researchers evaluated whether a panel of genetic alterations could identify this subset of patients. They also investigated whether the regular use of aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) affects the risk of developing esophageal cancer in people with Barrett's esophagus—other evidence suggests that NSAIDs may help to prevent several types of cancer, including esophageal cancer.

          What Did the Researchers Do and Find?

          The researchers took esophageal tissue samples from patients with Barrett's esophagus and looked for alterations in the genes encoding the tumor-suppressor proteins TP53 and CDKN2A. These proteins normally stop cells dividing but are often inactivated in cancer cells by mutation of one of the two gene copies that encode each of them and also loss of the other copy (so-called “loss of heterozygosity” or LOH). The researchers also looked for changes in the cellular DNA content of the samples (tumor cells often contain unusual amounts of DNA) and asked the study participants about their NSAID use before waiting to see which participants developed esophageal cancer. After 10 y, the participants whose tissue samples had LOH of the short arms (p) of Chromosome 17 or 9 (the sites of the genes encoding TP53 and CDKN2A, respectively), or an altered DNA content, were more likely to have developed esophageal cancer than those without these abnormalities; those whose samples contained all three abnormalities had the highest risk of developing esophageal cancer. Overall, just 12% of patients with no abnormalities but nearly 80% of patients with three abnormalities developed esophageal cancer. NSAID use reduced the risk of cancer development in all the participants, but its effect was greatest in those with three genetic abnormalities.

          What Do These Findings Mean?

          These findings suggest that the combined measurement of 17pLOH, 9pLOH, and cellular DNA content might be a powerful way to identify those patients with Barrett's esophagus who are most likely to develop esophageal cancer. They also suggest that NSAID use is associated with a reduced risk of esophageal cancer, particularly in patients with multiple genetic abnormalities. Because very few participants developed cancer during the study, these results need confirming in more patients. Also, the ability of NSAIDs to prevent the progression of Barrett's esophagus to esophageal cancer needs testing in multicenter randomized trials; the use of the panel of abnormalities described here to identify the people with Barrett's esophagus most at risk of developing esophageal cancer should facilitate such studies.

          Additional Information.

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            Risks of breast and ovarian cancer were determined for Ashkenazi Jewish women with inherited mutations in the tumor suppressor genes BRCA1 and BRCA2. We selected 1008 index cases, regardless of family history of cancer, and carried out molecular analysis across entire families. The lifetime risk of breast cancer among female mutation carriers was 82%, similar to risks in families with many cases. Risks appear to be increasing with time: Breast cancer risk by age 50 among mutation carriers born before 1940 was 24%, but among those born after 1940 it was 67%. Lifetime risks of ovarian cancer were 54% for BRCA1 and 23% for BRCA2 mutation carriers. Physical exercise and lack of obesity in adolescence were associated with significantly delayed breast cancer onset.
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              The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis.

              Patients with familial adenomatous polyposis have a nearly 100 percent risk of colorectal cancer. In this disease, the chemopreventive effects of nonsteroidal antiinflammatory drugs may be related to their inhibition of cyclooxygenase-2. We studied the effect of celecoxib, a selective cyclooxygenase-2 inhibitor, on colorectal polyps in patients with familial adenomatous polyposis. In a double-blind, placebo-controlled study, we randomly assigned 77 patients to treatment with celecoxib (100 or 400 mg twice daily) or placebo for six months. Patients underwent endoscopy at the beginning and end of the study. We determined the number and size of polyps from photographs and videotapes; the response to treatment was expressed as the mean percent change from base line. At base line, the mean (+/-SD) number of polyps in focal areas where polyps were counted was 15.5+/-13.4 in the 15 patients assigned to placebo, 11.5+/-8.5 in the 32 patients assigned to 100 mg of celecoxib twice a day, and 12.3+/-8.2 in the 30 patients assigned to 400 mg of celecoxib twice a day (P=0.66 for the comparison among groups). After six months, the patients receiving 400 mg of celecoxib twice a day had a 28.0 percent reduction in the mean number of colorectal polyps (P=0.003 for the comparison with placebo) and a 30.7 percent reduction in the polyp burden (the sum of polyp diameters) (P=0.001), as compared with reductions of 4.5 and 4.9 percent, respectively, in the placebo group. The improvement in the extent of colorectal polyposis in the group receiving 400 mg twice a day was confirmed by a panel of endoscopists who reviewed the videotapes. The reductions in the group receiving 100 mg of celecoxib twice a day were 11.9 percent (P=0.33 for the comparison with placebo) and 14.6 percent (P=0.09), respectively. The incidence of adverse events was similar among the groups. In patients with familial adenomatous polyposis, six months of twice-daily treatment with 400 mg of celecoxib, a cyclooxygenase-2 inhibitor, leads to a significant reduction in the number of colorectal polyps.

                Author and article information

                Role: Academic Editor
                PLoS Med
                PLoS Medicine
                Public Library of Science (San Francisco, USA )
                February 2007
                27 February 2007
                : 4
                : 2
                [1 ] Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
                [2 ] Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
                [3 ] Department of Medicine, University of Washington, Seattle, Washington, United States of America
                [4 ] Cellular and Molecular Oncogenesis Program, Wistar Institute, Philadelphia, Pennsylvania, United States of America
                [5 ] Department of Pathology, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, United States of America
                [6 ] Department of Gastroenterology, Virginia Mason Medical Center, Seattle, Washington, United States of America
                [7 ] Department of Pathology, University of Washington, Seattle, Washington, United States of America
                [8 ] Department of Epidemiology, University of Washington, Seattle, Washington, United States of America
                [9 ] Genome Sciences, University of Washington, Seattle, Washington, United States of America
                Genome Institute of Singapore, Singapore
                Author notes
                * To whom correspondence should be addressed. E-mail: pgal@
                06-PLME-RA-0387R2 plme-04-02-27
                Copyright: © 2007 Galipeau et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 13
                Research Article
                Evolutionary Biology
                Gastroenterology and Hepatology
                Genetics and Genomics
                Molecular Biology
                Public Health and Epidemiology
                Cancer: Gastroenterological
                Drugs and Adverse Drug Reactions
                Custom metadata
                Galipeau PC, Li X, Blount PL, Maley CC, Sanchez CA, et al. (2007) NSAIDs modulate CDKN2A, TP53, and DNA content risk for progression to esophageal adenocarcinoma. PLoS Med 4(2): e67. doi: 10.1371/journal.pmed.0040067



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