Gene Expression Signatures Differentiate Ovarian/Peritoneal Serous Carcinoma from Diffuse Malignant Peritoneal Mesothelioma

Abstract

Purpose: Ovarian/primary peritoneal serous carcinoma (OC/PPC) and diffuse peritoneal malignant mesothelioma (DMPM) are highly aggressive tumors that are closely related morphologically and histogenetically. It remains unclear whether both tumors are molecularly distinct neoplasms. The current study compared global gene expression patterns in OC/PPC and DMPM. Experimental Design: Ten OC/PPC and five DMPM effusions were analyzed for gene expression profiles using the Affymetrix U133 Plus 2 arrays and the dCHIP analysis program. Differentially expressed candidate genes were validated using quantitative real-time PCR and immunohistochemistry. Results: Unsupervised hierarchical clustering using all 54,675 genes in the array classified the samples into two groups: DMPM specimens versus OC/PPC specimens. A total of 189 genes that were differentially expressed in these two groups were selected based on statistical significance. Genes overexpressed in DMPM (n = 68) included calretinin, vitronectin, claudin 15, a 4 laminin, hyaluronan synthase 1, cadherin 11, RAB7, v-maf, and the epidermal growth factor^containing fibulin-like extracellular matrix protein 1. Genes overexpressed in OC/PPC (n = 121) included insulin-like growth factor II (IGF-II); IGF-II binding protein 3; cyclin E1; folate receptors 1 and 3; RAB25; MUC4; endothelin-1; CD24; kallikreins 6, 7, and 8; claudins 3, 4, and 6; Notch3; and MMP-7. Quantitative real-time PCR validated the differential expression of 13 genes, and immunohistochemistry confirmed the differences for four gene products. Conclusions: Expression profiling separates OC/PPC from DMPM and identifies a number of genes that are differentially expressed in these tumors. The molecular signatures unique to OC/PPC and DMPM should provide a molecular basis to study both tumors and new potential markers for facilitating their differential diagnosis.Diffuse malignant peritoneal mesothelioma (DMPM) is an aggressive cancer that originates from the native mesothelial cells of the peritoneal cavity. DMPM is less common than its pleural counterpart (9:1 ratio), differs in its gender predilection (roughly similar incidence in women and men), and has a weaker etiologic link to asbestos exposure (1, 2). The prognosis of DMPM patients has been extremely poor in earlier series, with median survival of 10 to 12 months (2). However, recent studies have shown improved survival (26-92 months) when DMPM patients are treated aggressively with combined debulking and preheated i.p. chemotherapy consisting of cisplatin, doxorubicin, and paclitaxel as major agents (2 -4). Recently, a response rate of 25% was achieved following pemetrexed treatment (5). The majority of DMPM are of the epithelioid type (6).Ovarian cancer (OC) is the most lethal gynecologic malignancy in the Western world and the fourth most frequent cause of cancer-related death in women (7). As DMPM, OC and the closely related and morphologically indistinguishable primary peritoneal carcinoma (PPC) are thought to develop from the peritoneal mesot...

Screening and identification of peritoneal metastasis-related genes of gastric adenocarcinoma using a cDNA microarray

“…When gene chip was applied in the beginning, the quality of microarray was not satisfactory from clone preparation, chip production, variations from hybridization, or inadequate data analysis. However, with improved chip quality and hybridization technique, recent microarray data showed good concordance with RT-PCR or Northern blot method with reliable biological meanings (Lee et al, 2005;Davidson et al, 2006). In the present study, upregulation of the S100A4 and CTNNB1 genes or downregulation of the PTEN gene in GC9811-P were also observed using RT-PCR analysis.…”

Small Interfering RNA Molecules Targeting Endothelin-Converting Enzyme-1 Inhibit Endothelin-1 Synthesis and the Invasive Phenotype of Ovarian Carcinoma Cells

“…Epithelial ovarian cancer is a heterogeneous group of neoplasms that can be divided into different histologic subgroups, each with its own underlying molecular genetic events (38)(39)(40).…”

“…This is most prominent in the serous or clear cell type histologic types that are known for their aggressive behavior (43). Studies in which effusions and the corresponding solid tumors were compared showed that cells in effusions are different from their counterparts in solid primary and metastatic lesions (40,42). By examining the expression of ECE-1 in solid tumors and in effusion samples, we found that it was significantly higher in solid tumors than in effusions, whereas ET-1 and ETA did not differ significantly between samples.…”

Pre-analytical issues in effusion cytology

“…This material has been extensively used for both gene expression array analyses of different cancers affecting the serosal cavities [73][74][75] and validation studies of the array data using qPCR [76][77][78][79][80][81][82].…”