Expression Profiling of Serous Low Malignant Potential, Low-Grade, and High-Grade Tumors of the Ovary

Abstract

Papillary serous low malignant potential (LMP) tumors are characterized by malignant features and metastatic potential yet display a benign clinical course. The role of LMP tumors in the development of invasive epithelial cancer of the ovary is not clearly defined. The aim of this study is to determine the relationships among LMP tumors and invasive ovarian cancers and identify genes contributing to their phenotypes. Affymetrix U133 Plus 2.0 microarrays (Santa Clara, CA) were used to interrogate 80 microdissected serous LMP tumors and invasive ovarian malignancies along with 10 ovarian surface epithelium (OSE) brushings. Gene expression profiles for each tumor class were used to complete unsupervised hierarchical clustering analyses and identify differentially expressed genes contributing to these associations. Unsupervised hierarchical clustering analysis revealed a distinct separation between clusters containing borderline and high-grade lesions. The majority of low-grade tumors clustered with LMP tumors. Comparing OSE with high-grade and LMP expression profiles revealed enhanced expression of genes linked to cell proliferation, chromosomal instability, and epigenetic silencing in high-grade cancers, whereas LMP tumors displayed activated p53 signaling. The expression profiles of LMP, low-grade, and high-grade papillary serous ovarian carcinomas suggest that LMP tumors are distinct from high-grade cancers; however, they are remarkably similar to low-grade cancers. Prominent expression of p53 pathway members may play an important role in the LMP tumor phenotype. (Cancer Res 2005; 65(22): 10602-12)

Mutation of ERBB2 Provides a Novel Alternative Mechanism for the Ubiquitous Activation of RAS-MAPK in Ovarian Serous Low Malignant Potential Tumors

“…However, the very substantial differences in gene expression between serous LMP and invasive tumors, observed in this study and others (8)(9)(10), confound such analyses. The identification of LLI tumors created the opportunity to examine gene expression differences between tumors that are very similar molecularly but differ phenotypically in terms of their invasiveness.…”

“…S2; GSEA analysis in Supplementary Table S3). To verify that the enrichment and overexpression of RAS-MAPK-related transcripts were, in fact, up-regulation in LMP tumors rather than a loss of these genes in invasive carcinomas, we compared our LMP dataset to normal ovarian surface epithelium data from Bonome et al (8). We found that RAS-MAPK pathway genes (enriched gene lists derived from Panther, DAVID, and GSEA) were highly overrepresented among genes that were overexpressed (2-fold greater expression, q < 0.05) in serous LMP compared with ovarian surface epithelium, with a statistical significance of P < 2.2eÀ16 (Fisher exact; see also Supplementary Fig.…”

“…Recently, our group and others have begun investigating the molecular profile of serous LMP tumors compared with the more common higher-grade serous carcinomas (7)(8)(9)(10). Overall, the results have suggested that LMP tumors follow a different process of cellular transformation compared with the majority of their invasive counterparts.…”

“…One striking feature of LMP tumors is the high rate of KRAS and BRAF mutations, both of which are thought to act primarily through the canonical RAS-MAPK (RAS-RAF-MEK-ERK-MAP kinase) pathway (3,7,(10)(11)(12)(13). Furthermore, many serous LMP tumors have been reported to have wild-type p53 and functional p53 signaling (8,14). It has been proposed that some serous LMP tumors progress to noninvasive or invasive micropapillary serous carcinomas, which may or may not progress further to become a high-grade invasive serous carcinoma (reviewed in refs.…”

Identification of molecular markers and signaling pathway in endometrial cancer in Hong Kong Chinese women by genome-wide gene expression profiling

“…As previously described, it utilizes two cycles of complementary DNA (cDNA) synthesis and in vitro transcription for the amplification of 50-100 ng of total RNA (Bonome et al, 2000). Labeled amplified RNA was then hybridized to the Affymetrix Human Genome U133 Plus 2.0 GeneChip (Affymetrix, Santa Clara, CA, USA), which contains over 55 000 probe sets representing more than 47 000 transcripts derived from well characterized genes.…”