Gains and Amplifications of c-myc, EGFR, and 20.q13 Loci in the No Dysplasia–Dysplasia–Adenocarcinoma Sequence of Barrett's Esophagus

Abstract

The progression of Barrett's esophagus to esophageal adenocarcinoma is often characterized by the accumulation of genetic abnormalities. The goal was to evaluate the copy number alterations of several oncogene loci, including 7p12 [epidermal growth factor receptor (EGFR)], 8q24 (c-myc), and 20q13 in the sequence of no dysplasia -dysplasia -adenocarcinoma of Barrett's esophagus. Fluorescence in situ hybridization with DNA probes for the centromeric region of chromosome 7 and the locus-specific regions of 7p12 (EGFR), 8q24 (c-myc), and 20q13 was applied on 99 brush cytology specimens of patients with Barrett's esophagus with different stages of dysplasia or esophageal adenocarcinoma. Gains (3-4 copies) of chromosome 17, 8q24 (c-myc), and 20q.13 loci were found in the low frequencies in nondysplastic Barrett's esophagus. Their frequencies increased with the stage of dysplasia and reached a high incidence in esophageal adenocarcinoma.Amplification (>4 copies) of at least 1 of the loci was observed in 14% of high-grade dysplasia and increased to 50% in esophageal adenocarcinoma (P = 0.015). The most frequently amplified locus was c-myc (18%), followed by 20q13 (13%) and EGFR (11%) in the highgrade dysplasia/esophageal adenocarcinoma cases. High amplification levels (>10 copies) of the loci were more frequent in esophageal adenocarcinoma (72%) compared with high-grade dysplasia (20%; P = 0.049). Amplifications of the c-myc, EGFR, and 20q12 loci may serve as diagnostic markers to identify patients with Barrett's esophagus with high-grade dysplasia or esophageal adenocarcinoma. Gains of the loci might be of value as prognostic markers because they are already present in nondysplasia cases and may precede the later event of the amplification as observed in high-grade dysplasia and esophageal adenocarcinoma. (Cancer Epidemiol Biomarkers Prev 2008;17(6):1380 -5)

Gene expression alterations in formalin-fixed, paraffin-embedded Barrett esophagus and esophageal adenocarcinoma tissues.

“…46 β-catenin, which was reduced at the mRNA level in this study, has a pattern of progressive loss of membranous protein expression with, in some studies, an increase in nuclear accumulation. [47][48][49][50][51][52] Variable findings have been reported for EGFR (epidermal growth factor receptor) expression 53 or amplification, 54 but the progressive reduction in EGFR expression in this study, together with the failure to identify significant differences in EGFR protein expression in normal, BE and EAC tissues in another study, 47 raise doubts regarding the applicability of EGFR-targeted therapy for this cancer type. 55 Another monoclonal antibody target, HER-2/erbB-2, was the most stably expressed gene in this study, with very similar mRNA levels in normal, BE and EAC tissues.…”

Early diagnosis of oesophageal cancer

“…Despite the availability of automated FISH systems, the price and need for specialist analysis prevent its routine use in a surveillance setting; however, automated systems may improve in the future. Amplification of c-myc, EGFR and the 20q12 loci have been proposed as prognostic markers for the development of dysplasia/AC and can be detected using FISH on brush cytology specimens (Rygiel et al, 2008). It should be remembered that FISH will not detect point mutations or hypermethylation.…”

Gastroesophageal Reflux Disease: Molecular Predictors in Neoplastic Progression of Barrett's Esophagus

“…Using PCR to evaluate gene expression, amplification of the EGFR locus was demonstrated in EAC without concomitant elevated expression in high-grade dysplasia with BE (Miller et al, 2003). However, another study did show gene locus amplification of EGFR in both BE associated high-grade dysplasia and EAC (Rygiel et al, 2008). There is also the possibility of a certain EGF polymorphism leading to an increased risk of EAC, as the specific EGFA61G G/G genotype has been shown to confer such a risk (Lanuti et al, 2008).…”