The human
growth factor receptor-bound protein 7 gene (GRB7), the founding member of a family of adaptor molecules has been shown to regulate cell migration and has been implicated in
tumor progression. GRB7 is localized in close proximity to the ERBB2 gene within an amplicon previously identified in Barrett's
adenocarcinoma (BCA). We evaluated gene amplification and
mRNA expression of GRB7 and ERBB2 in Barrett's
carcinoma and its associated precursor lesions to assess their possible role in Barrett's malignant transformation. Copy number and expression levels were analyzed by Q-PCR (GRB7, ERBB2) and QRT-PCR (GRB7, ERBB2) using TaqMan technology and fluorescence in situ hybridization (ERBB2) in a series of 24
laser-microdissected samples of Barrett's
carcinomas and 32 samples of associated premalignant lesions. Parallel analysis of gene copy number changes and expression levels demonstrated that GRB7 and ERBB2 displayed concomitant elevated expression levels and increased copy numbers in 32% of Barrett's
carcinomas. There was a correlation between GRB7 and ERBB2 in BCA at the
DNA level (r(s) = 0.76, p < 0.001) and the
mRNA level (r(s) = 0.89, p < 0.001). Moreover, coamplification (r(s) = 0.97, p < 0.001) and coexpression (r(s) = 0.81, p < 0.001) of GRB7 and ERBB2 are shown to be already present in a subset of BCA associated high-grade intraepithelial
neoplasia (HGIN), possibly reflecting a role of a concerted expression of GRB7 and ERBB2. No alterations, neither gene amplification nor overexpression were detected in Barrett's
carcinoma associated low grade intraepithelial
neoplasia (LGIN), intestinal
metaplasia (IM) and squamous epithelium, indicating that alterations of GRB7 and ERBB2 are late events in the
carcinogenesis of
Barrett's esophagus. These findings may be of particular interest because the transition from high grade intraepithelial
neoplasia to invasive
carcinoma is a crucial step in malignant transformation in Barrett's
carcinogenesis and might underline the putative role of GRB7 and ERBB2 in cell migration and
tumor invasion.