Gene expression patterns in ovarian carcinomas

Abstract

We used DNA microarrays to characterize the global gene expression patterns in surface epithelial cancers of the ovary. We identified groups of genes that distinguished the clear cell subtype from other ovarian carcinomas, grade I and II from grade III serous papillary carcinomas, and ovarian from breast carcinomas. Six clear cell carcinomas were distinguished from 36 other ovarian carcinomas (predominantly serous papillary) based on their gene expression patterns. The differences may yield insights into the worse prognosis and therapeutic resistance associated with clear cell carcinomas. A comparison of the gene expression patterns in the ovarian cancers to published data of gene expression in breast cancers revealed a large number of differentially expressed genes. We identified a group of 62 genes that correctly classified all 125 breast and ovarian cancer specimens. Among the best discriminators more highly expressed in the ovarian carcinomas were PAX8 (paired box gene 8), mesothelin, and ephrin-B1 (EFNB1). Although estrogen receptor was expressed in both the ovarian and breast cancers, genes that are coregulated with the estrogen receptor in breast cancers, including GATA-3, LIV-1, and X-box binding protein 1, did not show a similar pattern of coexpression in the ovarian cancers.

Figure 1.

Unsupervised hierarchical clustering of ovarian cell lines and ovarian cancers. Cell lines were not coclustered with the tumor specimens, because these cell lines have a very prominent proliferation cluster (Perou et al., 1999; Ross et al., 2000) that significantly influences the clustering of the tumor samples if the two sample sets are not analyzed separately. Ovarian cancer specimens and cell lines were clustered based on variation of expression of 1558 genes, as detailed in MATERIALS AND METHODS. Genes were clustered based on similarity in their expression patterns among these cancers. Eight gene clusters are highlighted in this display. (A) Lymphocyte cluster, (B) epithelial/keratin expression, (C) ascites signature, (D) clear cell overexpressed genes, (E) extracellular matrix/stromal cluster, (F) proliferation cluster, (G) heterogeneity across ovarian cases, and (H) clear cell under-expressed genes. The color contrast of the scale bar indicates the fold of gene expression change in log2 space (numbers above the bar).

Figure 2.

Zoomed images of selected regions of Figure 1, which clustered the ovarian specimens based on variation of expression of 1558 genes. (A) Immune cell cluster, (B) epithelial/keratin expression (C) ascites signature, (D) clear cell overexpressed genes, (E) invasion/stromal cluster, (F) proliferation cluster, (G) heterogeneity across ovarian cases, and (H) clear cell underexpressed genes.

Figure 3.

Clear cell signature determined by hierarchical clustering. Genes were selected as detailed in Figure 1 and in MATERIALS AND METHODS. An expanded view of the gene expression patterns (A) over- or (B) underexpressed in clear cell cancers identified using simple hierarchical clustering from Figure 1 is shown.

Figure 4.

Clustering of breast and ovarian carcinoma cases. 68 breast and 57 ovarian cases were co-clustered to discern both similarities and disparities between the two sample sets. An ovarian-specific set of highly expressed transcripts was identified in comparison to breast across the 3363 transcripts. The color contrast of the scale bar indicates the fold of gene expression change in log2 space (numbers above the bar).

Figure 5.

Immunohistochemistry: ovarian cancer tissue arrays comprised of both serous (left panel) and clear cell (right panel) ovarian cancers. Hematoxylin and eosin staining is shown in the top panel. Staining of a representative case of serous and clear cell, respectively, were stained with antibodies against EPCAM, annexin IV, HE4, and WT1.