Coamplification and coexpression of GRB7 and ERBB2 is found in high grade intraepithelial neoplasia and in invasive Barrett's carcinoma

Abstract

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.

Assessment of ErbB2 (Her2) in oesophageal adenocarcinomas: summary of a revised immunohistochemical evaluation system, bright field double in situ hybridisation and fluorescence in situ hybridisation

“…13 Others report similar rates of ErbB2 positivity in oesophageal adenocarcinomas, highlighting the impact of ErbB2 amplification and ERBB2 overexpression during the malignant progression of Barrett's metaplasia to invasive cancer. [27][28][29] The relatively high number of ErbB2-positive cases in our study compared with other reports may be due to the definition of ErbB2 positivity, which was based on the guidelines of the ToGA study and the EMEA for trastuzumab (Herceptin r ) treatment for advanced gastric cancer. This recommendation requires a ErbB2 score of 3 þ by immunohistochemistry or an amplification level of Z2 (ErbB2/Chr17) even in small tumour cell clusters, 10 which is different from the breast carcinoma requirements, in which cases with a ErbB2/ Chr17 ratio between 1.8 and 2.2 are considered as equivocal and ErbB2 expression is less heterogeneous.…”

Activation of Growth Factor Receptors in Esophageal Cancer—Implications for Therapy

“…The reasons for these contradictory results need to be addressed in future studies. It has been proposed that coexpression of the adaptor protein Grb7 and HER-2 may contribute to an invasive tumor phenotype [37,67], consistent with a role for Grb7 in cell migration.…”

Molecular Dissection of 17q12 Amplicon in Upper Gastrointestinal Adenocarcinomas

“…We recently showed that PPP1R1B/DARPP-32 is a novel cancer gene with a potent antiapoptotic potential that may contribute to the drug resistance and poor outcome phenotype in UGCs (37). Amplification and expression of ERBB2 and GRB7 was recently reported in Barrett's adenocarcinoma (38)(39)(40). However, these studies lacked data related to the expression of other genes that are between or at the boundaries of ERBB2 and GRB7.…”