Clonal expansion and loss of heterozygosity at chromosomes 9p and 17p in premalignant esophageal (Barrett's) tissue

Background: Abnormalities involving the p16 (also known as cyclin-dependent kinase N2 [CDKN2], p16 [INK4a], or MTS1) and p53 (also known as TP53) tumo r suppressor genes are highly prevalent in esophageal adenocarcinomas. Loss of heterozygosity (LOH) at 9p21 and 17p13 chromosomes (locations for p16 a nd p53 genes, respectively) is frequently observed in the premalignant cond ition, Barrett's esophagus, We studied extensively the distribution and het erogeneity of LOH at 9p and 17p chromosomes throughout the Barrett's segmen t in patients who have not yet developed esophageal adenocarcinoma, Methods : We evaluated 404 samples from 61 consecutive patients enrolled in the Sea ttle Barrett's Esophagus Study from February 1995 through September 1998. A ll patients had high-grade dysplasia but no diagnosis of cancer. The sample s were assayed for LOH at 9p and 17p chromosomes after amplification of gen omic DNA by use of polymerase chain reaction and DNA genotyping, The cell f ractions were purified by flow cytometry on the basis of DNA content and pr oliferation-associated antigen labeling, Association between LOH at 9p and LOH at 17p with now cytometric abnormalities was determined by chi-squared test, and logistic regression models were used to model and test for the ex tent to which a particular genotype was found in 2-cm intervals. Results an d Conclusions: LOH at 9p and 17p chromosomes are highly prevalent somatic g enetic lesions in premalignant Barrett's tissue. LOH at 9p is more common t han LOH at 17p in diploid samples and can be detected over greater regions of Barrett's epithelium, In most patients with high-grade dysplasia, the Ba rrett's mucosa contains a mosaic of clones and subclones with different pat terns of LOH, Some clones had expanded to involve extensive regions of Barr ett's epithelium. LOH at 9p and 17p chromosomes may be useful biomarkers to stratify patients' risk of progression to esophageal cancer.