Conclusions: Our data are consistent with the possibility that a limited number of markers in combination might identify >99% of epithelial ovarian cancers despite the heterogeneity of the disease.

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...