High‐resolution analysis of genomic alteration on chromosome arm 8p in urothelial carcinoma

Abstract

Loss of chromosome arm 8p, sometimes in combination with amplification of proximal 8p, is found in urothelial carcinoma (UC) and other epithelial cancers and is associated with more advanced tumor stage. We carried out array comparative genomic hybridization on 174 UC and 33 UC cell lines to examine breakpoints and copy number. This was followed by a detailed analysis of the cell lines using fluorescence in situ hybridization (FISH) and, in some cases, M-FISH, to refine breakpoints and determine translocation partners, heterozygosity analysis, and analysis of expression of selected genes. We showed an overall pattern of 8p loss with reduced heterozygosity and reduced gene expression. Amplification was seen in some samples and shown in the cell line JMSU1 to correlate with overexpression of ZNF703, ERLIN2, PROSC, GPR124, and BRF2. Apart from the centromere, no single breakpoint was overrepresented, and we postulate that frequent complex changes without consistent breakpoints reflect the need for alterations of combinations of genes. The region around 2 Mb, which was homozygously deleted in one cell line and includes the gene ARHGEF10 and the micro-RNA hsa-mir-596, is one candidate tumor suppressor gene region.

A cluster of cooperating tumor-suppressor gene candidates in chromosomal deletions

“…S3). Also validated in these experiments were the candidate TSGs Scara5, which negatively regulates focal adhesion kinase signaling (19), and Arhgef10, previously implicated in breast and urothelial carcinomas (5,6) (Fig. S3).…”

“…Previously, we validated the 8p gene DLC1, encoding a Rho GAP, as a TSG using a mouse model of hepatocellular carcinoma (HCC), confirming that its attenuation can serve as a driving oncogenic event (3). Although DLC1 is at an epicenter of deletions, these deletions are frequently much larger and reduce the dosages of tens or hundreds of genes, often encompassing the entire 8p22 cytoband and beyond (2,5,6). Indeed, multiple candidate TSGs have been proposed in the region (5)(6)(7)(8).…”

“…Although DLC1 is at an epicenter of deletions, these deletions are frequently much larger and reduce the dosages of tens or hundreds of genes, often encompassing the entire 8p22 cytoband and beyond (2,5,6). Indeed, multiple candidate TSGs have been proposed in the region (5)(6)(7)(8). Here we explore the hypothesis that chromosome 8p deletions arise owing to selection for the attenuation of multiple genes.…”

ARHGEF10 directs the localization of Rab8 to Rab6-positive executive vesicles

“…Thus, in the peripheral nervous system, ARHGEF10 might act to establish myelin sheaths by regulating membrane trafficking. Recently, various studies have proposed associations of ARHGEF10 mutations with various diseases, including Charcot-Marie-Tooth disease, epithelial cancer, schizophrenia and atherothrombotic stroke (Cooke et al, 2008;Tabarés-Seisdedos and Rubenstein, 2009;Matsushita et al, 2010;Williams et al, 2010;Yin et al, 2011;Ekenstedt et al, 2014;Boora et al, 2015). More precise studies of ARHGEF10 might identify therapeutic targets for these diseases.…”

Large-Scale Copy-Number Alterations in Chicken Ovarian Cancer

“…The amplified CNV genomic region between 220266 and 2252857 of the chicken chromosome 12 contains the loci for ERLIN2, PROSC, and GPR124, which correspond to human chromosome 8p. This region has been reported to be amplified or deleted in urothelial carcinoma and other epithelial cancers (Williams et al, 2010). Interleukin 1 (IL1), which is contained in an amplified region in our study, is involved in the carcinogenesis of several cancers (Hefler et al, 2002;Sehouli et al, 2002;Hefler et al, 2005), and it appears to increase the proliferative activity of ovarian cancer and enhance cytotoxicity (Hefler et al, 2002;Ioana Braicu et al, 2007).…”