Genomic analysis of early adenocarcinoma of the esophagus or gastroesophageal junction: Tumor progression is associated with alteration of 1q and 8p sequences

Abstract

Early (T1 stage) adenocarcinoma of the esophagus or gastroesophageal junction is a potentially curable disease. We analyzed the genomic spectra of 33 early neoplastic lesions after subdividing the tumors into six depths of invasion (T1-mucosal, m1-m3; T1-submucosal, sm1-sm3). Two subgroups were defined, T1m1-sm1 (n = 18) and T1sm2-sm3 (n = 15). The latter group is associated with frequent lymphatic spread and a high percentage of local and/or distant recurrence. Comparative genomic hybridization with a genomewide 3,500-element BAC-PAC array revealed a characteristic gastroesophageal adenocarcinoma pattern of changes, with losses on chromosome arms 4pq, 5q, 8p, 9p, 17p, and 18q and gains on 1q, 6p, 7pq, 11q, 15q, 17q, and 20pq. However, when the two groups were compared, the following BAC clones showed significantly more alterations in the T1sm2-sm3 group: RP11-534L20 (1q32.1) and RP11-175A4 (6p21.32), showing gains, and RP11-356F24, RP11-433L7, and RP11-241P12 (all at 8p), showing losses. Gain of RP11-534L20 (1q32.1) and loss of RP11-433L7 (8p22) were associated not only with a recurrence-free period (P = 0.0007 and 0.007, respectively), but also with regional lymphatic dissemination (P = 0.005 and 0.003, respectively). These DNA clones can be considered genomic markers for the aggressive behavior of early esophageal and gastroesophageal junction adenocarcinoma.

DNA copy number alterations correlate with survival of esophageal adenocarcinoma patients

“…Studies carried out by classical CGH have demonstrated multiple chromosomal copy number changes, including gains in chromosomes 6q, 7p, 7q, 8q, 11q, 15q, 17q, and 20q, as well as losses at chromosomes 1p, 3p, 4p, 4q, 5q, 8p, 9p, 17p, and 18q. [4][5][6][7][8]14 However, the minimal amplified region detected by conventional CGH usually spans several megabases, making it difficult to identify specific candidate genes involved in tumor development.…”

“…Recurrent DNA gains on chromosome 6p have been reported in esophageal adenocarcinoma, 6,7,15 but to date they have not been well characterized. Our analysis revealed that besides VEGF amplification (6p12) common to 50% of esophageal adenocarcinoma samples, other alterations were found exclusively or mostly in the r20-month survival subgroup, such as gain of KIAA0170 and IER3 genes at 6p21.3.…”

“…However, when the total number of chromosomal imbalances was correlated to patient survival, a significant association (P ¼ 0.002) between the total number of gains/losses and survival was found. In particular, by dividing the patients according to their median survival time (20 months), we found that the mean number of quantitatively altered genes per tumor was 20.7 (range 6-33) in patients with a survival r20 months (17 patients), compared to 10.1 (range [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] in patients with a survival 420 months (16 patients) ( Table 2). Similarly, stratification of the patients according to the median number of chromosomal imbalances (12 aberrations), showed a good association with survival (P ¼ 0.014).…”

“…Gains were also frequently observed on chromosomes 6q, 7p, 7q, 8q, 11q, 15q, and 17q; recurrent losses were described on chromosomes 1p, 3p, 4p, 4q, 5q, 8p, 9p, 17p, and 18q. [4][5][6][7][8] The majority of these studies used conventional comparative genomic hybridization (chromosomal-CGH), making identification of the genes involved difficult; to date, the genetic alterations associated with disease onset and progression remain largely unknown.…”

Mistaken Identity of Widely Used Esophageal Adenocarcinoma Cell Line TE-7

“…The spot intensities were measured with GenePix Pro 5.1 software (Axon Instruments). Further analyses were done using Microsoft Excel 2000 (15,16).…”