Whole genome analysis of copy number changes in Barrett's esophagus and esophageal adenocarcinoma.

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Copy number changes (amplifications and deletions) are hallmarks of solid tumors, but how these genetic alterations develop and evolve in premalignant tissues have been difficult to determine. Patients with the premalignant condition Barrett's esophagus (BE) are at risk for developing esophageal adenocarcinoma (EA). The standard of care for patients with BE is periodic endoscopic surveillance with biopsy for the early detection of cancer, allowing characterization of the genetic and epigenetic alterations that occur during neoplastic progression. We have examined copy number alterations on a whole genome scale in biopsies from 82 patients with BE that had not progressed to cancer and in 13 patients who developed EA. Copy number changes were detected by array comparative genomic hybridization (aCGH) on 4,190 element BAC arrays. Data from the arrays were denoised and regions of gain and loss identified using a non-parametric, wavelet approach. Genetic instability increased during disease progression, with the average number of BACs with copy number changes increasing significantly from the less than high grade dysplasia (<HGD) patients (37 BACs per biopsy), to high grade dysplasia (HGD) patients (176 BACs), to cancer (1479 BACs) (p<0.01). While few copy number alterations were detected in <HGD samples, those that did occur involved critical biological pathways, including the retinoblastoma/cell cycle control pathway (losses at CDKN2a on chromosome 9p in 50% of the patients and at CDKN2c on 1p in 46%) and mediators of inflammation (loss of Cox2 on 1q in 18% of patients). HGD samples were characterized by more frequent and more extensive copy number changes, likely reflecting inactivation of p53 during neoplastic progression. EA samples were characterized by extensive genomic alterations, frequently involving gains and losses of arms or whole chromosomes, as well as regions of high level amplification (e.g. high level ERBB2 amplification in 40% of EA patients) . Taken together, this study identifies copy number alterations that can be evaluated as markers of early cancer risk, biological pathways that are being targeted for disruption during neoplastic progression, and potential molecular targets for preventive and neoadjuvant therapies.