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It has been hypothesized that neoplastic progression develops as a consequence of an acquired genetic instability and the subsequent evolution of clonal populations with accumulated genetic errors. Accordingly, human cancers and some premalignant lesions contain multiple genetic abnormalities not present in the normal tissues from which the neoplasms arose. Barrett oesophagus (BE) is a premalignant condition which predisposes to oesophageal adenocarcinoma (EA) that can be biopsied prospectively over time because endoscopic surveillance is recommended for early detection of cancer. In addition, oesophagectomy specimens frequently contain the premalignant epithelium from which the cancer arose. Neoplastic progression in BE is associated with alterations in TP53 (also known as p53) and CDKN2A (also known as p16) and non-random losses of heterozygosity (LOH). Aneuploid or increased 4N populations occur in more than 90-95% of EAs, arise in premalignant epithelium and predict progression. We have previously shown in small numbers of patients that disruption of TP53 and CDKN2A typically occurs before aneuploidy and cancer. Here, we determine the evolutionary relationships of non-random LOH, TP53 and CDKN2A mutations, CDKN2A CpG-island methylation and ploidy during neoplastic progression. Diploid cell progenitors with somatic genetic or epigenetic abnormalities in TP53 and CDKN2A were capable of clonal expansion, spreading to large regions of oesophageal mucosa. The subsequent evolution of neoplastic progeny frequently involved bifurcations and LOH at 5q, 13q and 18q that occurred in no obligate order relative to each other, DNA-content aneuploidy or cancer. Our results indicate that clonal evolution is more complex than predicted by linear models. [ABSTRACT FROM AUTHOR]

A dramatic increase in the incidence of esophageal adenocarcinoma has occurred among men in the United States over the last two decades. The underlying reasons remain largely unknown, although the increasing prevalence of obesity likely plays a role. Most adenocarcinomas arise in a metaplastic epithelium termed Barrett's esophagus (BE) that develops in approximately 10% of persons who have chronic gastroesophageal reflux. Persons with BE are at high risk (0.5-1.0%/year) of progressing to cancer. In a cross-sectional study of 429 persons with BE, we evaluated the associations between increased body mass index, anthropometric measures, cigarette smoking, use of nonsteroidal anti-inflammatory drugs (NSAIDs) and markers of increased risk, including aneuploidy, increased 4N fraction, loss of heterozygosity (LOH) of 17p and 9p alleles, and high-grade dysplasia (HGD). In logistic regression models adjusting for age, gender, NSAID use, and cigarette smoking, increasing waist:hip ratio was related to increasing risk of aneuploidy (trend P = 0.01), 17p LOH (trend P = 0.005), and 9p LOH (trend P = 0.007). The odds ratios comparing highest to lowest quartiles were 4.3 [95% confidence interval (CI), 1.2-15.6] for aneuploidy, 3.9 (95% CI, 1.3-11.4) for 17p LOH, and 2.7 (95% CI, 1.2-6.3) for 9p LOH. A nonsignificant trend was also observed for increased 4N fraction, whereas little association was found for HGD. Similar patterns of risk were noted for other anthropometric measures such as waist:thigh and abdomen:thigh ratios. There was no evidence that elevated body mass index increased risk of any of the biomarkers. Suggestive evidence also was found for a protective effect of NSAID use. The odds ratios for current users, compared with those who never used NSAIDs regularly, were 0.6 (95% CI, 0.3-1.4) for increased 4N, 0.6 (95% CI, 0.3-1.3) for aneuploidy, 0.3 (95% CI, 0.1-0.7) for 17p LOH, and 0.7 (95% CI, 0.4-1.2) for HGD. There was no association between NSAID use and risk of 9p LOH. We conclude that an abdominal distribution of body fat, which is more common in men and is termed male-pattern obesity, may be a strong predictor of risk of neoplastic progression among persons with BE and may account in part for the male predominance of BE and esophageal adenocarcinoma. We also conclude that NSAID use may reduce the risk of progression to cancer in this population. Prospective studies are needed to confirm these results.