Chromosomal imbalances in Barrett's adenocarcinoma and the metaplasia-dysplasia-carcinoma sequence

To characterize cytogenetic alterations found in Barrett's adenocarcinoma ( BA) and, more importantly, its premalignant stages, we studied chromosomal imbalances in various lesions in the histologically proposed metaplasia-dys plasia-carcinoma sequence using comparative genomic hybridization (CGH). Us ing 30 esophageal adenocarcinoma resection specimens, we were able to study 30 areas of Barrett's adenocarcinoma and 8 lymph node metastases (LN). In addition, we investigated 25 premalignant lesions adjacent to BA derived fr om a subset of 14 resection specimens including 11 areas of high grade dysp lasia (HGD), 8 areas of low grade dysplasia (LGD), and 6 areas of intestina l metaplasia (IM), which were laser-microdissected and studied with CGH. To validate the CGH findings, fluorescence ill situ hybridization analysis on 13 BA with probes specific for HER-2/neu and 20q13.2 were performed. The c hromosomal alterations most often identified in BA were: gains on 8q (80%), 20q (60%), 2p, 7p and 10q (47% each), Gp (37%), 15q (33%) and 17q (30%). L osses were observed predominantly on the Y-chromosome (76%), 4q (50%), 5q a nd 9p (43% each), 18q(40%), 7q (33%) and 14q (30%). High-level amplificatio ns were observed on 8q23-qter, 8p12-pter, 7p11-p14, 7q21-31, 17q11-q23. Rec urrent chromosomal changes were also identified in metaplastic (gains on 8q , Gp, 10q, losses on 13q, Y, 9p) and dysplastic epithelium (gains on 8q, 20 q, 2p, 10q, 15q, losses on Y, 5q, 9P, 13q, 18q). Novel amplified chromosoma l regions on chromosomes 2p and 10q were detected in both Barrett's adenoca rcinoma and premalignant lesions. An increase of the average number of dete cted chromosomal imbalances from IM (7.0 +/- 1.7), to LGD (10.8 +/- 2.2), H GD (13.4 +/- 1.1), BA (13.3 +/- 1.4), and LN(22 +/- 1.2) was seen. Although the detection of common chromosomal alterations in premalignant lesions an d adjacent carcinomas suggest a process of clonal expansion, the occurrence of several chromosomal changes in an apparently random order relative to o ne another is striking evidence that clonal evolution is more complex than would be predicted by Linear models. This is probably a reflection of the e xistence of many divergent neoplastic subpopulations and highlights one of the main problems associated with surveillance of Barrett's patients, namel y sampling error.