Patterns of Gene Expression in Different Histotypes of Epithelial Ovarian Cancer Correlate with Those in Normal Fallopian Tube, Endometrium, and Colon

Abstract

Purpose: Epithelial ovarian cancers are thought to arise from flattened epithelial cells that cover the ovarian surface or that line inclusion cysts. During malignant transformation, different histotypes arise that resemble epithelial cells from normal fallopian tube, endometrium, and intestine. This study compares gene expression in serous, endometrioid, clear cell, and mucinous ovarian cancers with that in the normal tissues that they resemble. Experimental Design: Expression of 63,000 probe sets was measured in 50 ovarian cancers, in 5 pools of normal ovarian epithelial brushings, and in mucosal scrapings from 4 normal fallopian tube, 5 endometrium, and 4 colon specimens. Using rank-sum analysis, genes whose expressions best differentiated the ovarian cancer histotypes and normal ovarian epithelium were used to determine whether a correlation based on gene expression existed between ovarian cancer histotypes and the normal tissues they resemble. Results: When compared with normal ovarian epithelial brushings, alterations in serous tumors correlated with those in normal fallopian tube (P = 0.0042) but not in other normal tissues. Similarly, mucinous cancers correlated with those in normal colonic mucosa (P = 0.0003), and both endometrioid and clear cell histotypes correlated with changes in normal endometrium (P = 0.0172 and 0.0002, respectively). Mucinous cancers displayed the greatest number of alterations in gene expression when compared with normal ovarian epithelial cells. Conclusion: Studies at a molecular level show distinct expression profiles of different histologies of ovarian cancer and support the long-held belief that histotypes of ovarian cancers come to resemble normal fallopian tube, endometrial, and colonic epithelium. Several potential molecular markers for mucinous ovarian cancers have been identified. Most investigators believe that epithelial ovarian cancersdevelop from a single layer of cells that cover the ovary or that line inclusion cysts immediately beneath the ovarian surface (1). Despite their origin from flattened cells without distinctive features, ovarian cancers differentiate during malignant transformation into four major histotypes: serous, endometrioid, clear cell, and mucinous. Pathologists have pointed to a morphologic resemblance between these histotypes and the differentiation of normal mucosal cells in the gynecologic and intestinal tracts. Thus, serous carcinomas are thought to resemble fallopian tube epithelium, endometrioid carcinomas to normal endometrium, clear cell carcinomas to vaginal rests, and mucinous carcinomas to normal endocervical glands or intestinal mucosa. Molecular alterations that contribute to these morphologic changes have not been adequately studied.Previous reports have shown that tumors of different histotypes can have distinct characteristics with regard to epidemiology, genetic abnormalities, expression of tumor markers, and response to chemotherapy (1 -3). Parity, breastfeeding, and oral contraceptive use have been associated with dec...

Identification of an ovarian clear cell carcinoma gene signature that reflects inherent disease biology and the carcinogenic processes

“…Advances in molecular characterization of histological types has allowed for development of targeted molecular therapies based on the specific subtype (Perou et al, 2000;van 't Veer et al, 2002). To reveal the molecular background of OCCC, several microarray studies identified genes that are specifically expressed in OCCC (Schwartz et al, 2002;Schaner et al, 2003;Tsuchiya et al, 2003;Marquez et al, 2005;Zorn et al, 2005). However, in each case only the respective original microarray data set was analyzed, and thus these reports did not test for reproducibility of the OCCC gene expression profiles that each defined.…”

“…These 437 overlapping probe sets clearly detect OCCC-specific tumor clusters using hierarchical clustering within GSE6008 (d) and KyotoOv38 (e). In the analysis of the PMID16144910 data set (Marquez et al, 2005), a tumor cluster containing six OCCC tumors was clearly detected using the OCCC signature (overlapping OCCC probe set) (f, left), whereas the nonoverlapping probe sets from GSE6008 (f, middle) and from KyotoOv38 (f, right) did not generate such a defined OCCC tumor cluster. For GSE2109, the overlapping OCCC signature generated gene clusters enriched for OCCC tumors (g, left), whereas the nonoverlapping probe sets did not detect an OCCC-specific tumor cluster (g, middle and right).…”

“…Epithelial ovarian cancers are thought to develop from deregulation of cells within the ovarian surface epithelia and differentiate into four major histological subtypes: serous (OS), mucinous (OM), endometrioid (OE) adenocarcinomas and ovarian clear cell carcinomas (OCCCs) during malignant transformation. Recent reports also indicate that ovarian cancers, especially of clear cell and endometrioid histologies, arise from endometriotic epithelial cells in endometriosis (Dinulescu et al, 2005;Marquez et al, 2005). Increasing evidence suggests that development of various subtypes of ovarian cancer is attributable to different etiologies, although the precise molecular processes have not yet been fully elucidated (Cheng et al, 2005;Dinulescu et al, 2005).…”

“…In ovarian cancer, several studies have reported genes that are differentially expressed in OCCC. However, there was little overlap among the genes identified in these studies, and thus a reproducible gene signature specific for OCCC has not yet been identified (Schwartz et al, 2002;Schaner et al, 2003;Tsuchiya et al, 2003;Marquez et al, 2005;Zorn et al, 2005).…”

PAX2-null secretory cell outgrowths in the oviduct and their relationship to pelvic serous cancer

“…8,10,16 However, it is known that in addition to loss of TP53 function, numerous other disturbances in gene expression characterize high-grade serous cancers, and it is logical to presume that precursors contain some of these functional alterations. 17,18 One of these genes, PAX2, has been shown to be down-regulated in both high-grade mü llerian (endometrioid or serous) pelvic carcinomas and in benign and neoplastic endometrium. 16,[19][20][21] Recently, we identified a second form of SCOUT in the oviduct that exhibited normal TP53 genotype but on further analysis, frequently showed a loss or reduction of PAX2 immunostaining.…”