Loss ofCDC4/FBXW7in Gastric Carinoma

摘要

Background:CDC4/FBXW7, encoding a ubiquitin ligase, maps to 4q32 and has been implicated as a tumor suppressor gene and therapeutic target in many tumor types. Mutations in colonic adenomas, and the frequent losses on 4q described in gastric cancer prompt speculation about the role ofCDC4/FBXW7in gastric carcinogenesis.Methods: We assessed the role ofCDC4/FBXW7in gastric cancer, through loss of heterozygosity (LOH) and multiplex ligation-dependent probe amplification (MLPA) on 47 flow-sorted gastric carcinomas including early-onset gastric cancers (EOGC) and xenografted conventional gastric carcinomas. Ploidy analysis was carried out on 39 EOGCs and immunohistochemistry ofCDC4/FBXW7and its substrates c-myc, c-jun, Notch and cyclin E was performed on 204 gastric carcinomas using tissue microarrays (TMAs). Sequence analysis ofCDC4/FBXW7was carried out on gastric carcinoma cell lines and xenografts.Results: Loss of heterozygosity ofCDC4/FBXW7occurred in 32% of EOGCs, and correlated with loss of expression in 26%. Loss of expression was frequent in both EOGC and conventional gastric cancers. NoCDC4/FBXW7mutations were found and loss ofCDC4/FBXW7did not correlate with ploidy status. There was a significant correlation between loss ofCDC4/FBXW7expression and upregulation of c-myc.Conclusions: Loss ofCDC4/FBXW7appears to play a role in both EOGC and conventional gastric carcinogenesis, and c-myc overexpression is likely to be an important oncogenic consequence ofCDC4/FBXW7loss.