Abstract 1993: Global correlation analysis of HOXC6 expression in ovarian cancer

Abstract Introduction: HOXC6 is a member of the HOX gene family known to be dysregulated in many cancers. We previously reported gene and protein down-regulation of HOXC6 in ovarian cancer tissue and serum of high-grade serous carcinoma patients. This study evaluates the relationship of the HOXC6 gene expression with other genes from transcriptional microarray analysis of 92 ovarian tissues. Methods: Transcriptional microarray data from ovarian tissue was analyzed from 67 whole tissue samples and 25 micro-dissected samples. The 25 samples consisted of 9 malignant tumor tissues, 9 normal epithelia (NE) tissues and 7 Benign Tumor tissues. Genes with significant direct or reverse correlations to HOXC6 were initially identified from the 67-sample set (FDR < 0.05). Correlated genes identified in the 67-sample set were then reanalyzed to reconfirm their significance against the HOXC6 in 25-sample set (FDR < 0.05). To verify validity of correlations in cancer, expression values of genes in this second group were compared between NE and malignant samples using ANOVA (FDR < 0.05). This analysis pipeline identified 116 genes, which were characterized by STRING-DB 9.1 for protein-protein interactions and GO enrichment analysis. 65 of the 116 genes with a fold change (FC) magnitude > 2.0 were used in unsupervised hierarchical clustering against both NE and malignant samples. Results: The absolute values of correlation coefficients (|r|) in 116 significant genes ranged from 0.43-0.81; 33 had (|r|) > 0.70, and 65 had |FC| > 2.0. Of note because of their known association to ovarian cancer, this analysis revealed PBX3, MAL2, TPD52, ZEB2, PTTG1, KLK7, and KLK8. GO enrichment analysis identified developmental process (36 genes), cell differentiation (34), anatomical structure development (36), and regulation of signaling (27) consistent with HOXC6 known functions (FDR < 0.05). Protein-protein interaction networks revealed SMAD3 to be the central node with the largest cluster of connectivity linked to other HOXC6 correlated genes including PAX8, ZEB2 and UCHL5. Unsupervised hierarchical clustering analysis clearly distinguished between NE obtained from non-tumorous and NE obtained from tumorous tissues. Discussion: Overall this analysis demonstrates a strong correlation between HOXC6 expression in ovarian tissue and multiple developmental genes. The hierarchical clustering results may indicate that effects of the reported genes are not limited to the tumor tissue and can be traced back to normal epithelial cells. Therefore, future study of large sample sets of micro-dissected malignant and nearby normal epithelia – to identify underlying developmental pathways in ovarian cancer – will increase understanding of growth mechanisms of ovarian tumors and their interaction with normal cells in the microenvironment. Our previous work along with these new findings could potentially be used for future study of identifying ovarian cancer specific biomarkers. Citation Format: Pourya Naderi Yeganeh, Zahra Bahrani-Mostafavi, Christine Richardson, David L. Tait, M. Taghi Mostafavi. Global correlation analysis of HOXC6 expression in ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1993. doi:10.1158/1538-7445.AM2015-1993