Abstract 4024: Ten degrees of separation: novel genes affecting outcome in ovarian cancer.
Authors: Zand Behrouz , Ivan Cristina , Pecot Chad V. , Rupaimoole Rajesha , Dalton Heather J. , Bottsford-Miller Justin , Hu Wei , Nick Alpa M. , Sood Anil K. 
Published: August 2014

Objective: To identify genomic predictors of overall survival of women with high grade serous ovarian cancer based on best separation overall survival Kaplan-Meier curves

Methods: Comprehensive data analysis of the TCGA dataset of high grade serous epithelial ovarian cancer was carried out with a “training” (n= 375) and “validation” (n= 188) data sets. The R-code was written specifically to identify all genes with high expression that gave the greatest predictive potential for patient survival. The top ten cases with lowest sums of the log rank test p-values obtained for training and validation sets were chosen to be included with Kaplan-Meier survival curves for analysis.

Results: The ten genes with high expression that had the smallest p-values in their respective order were: SLC6A1, LIPK, EHBP1, SUSD5, PEX3, SLC22A3, RABGEF1, PPM2C, KIAA1219, and GALNT10. The range of p-value sum ranged from 1.77E-3 to 2.09E-3. The lowest p-value was for SLC6A1, which encodes for GABA Transporter-1 that removes GABA from extracellular to intracellular space. Interestingly, four of the 10 genes predictive for poor outcome are directly involved in cell metabolism: LIPK, PPM2C, PEX3, and GALNT10. The median OS of the high gene expression group ranged from 38 to 48 months. The median OS of the low gene expression group ranged from 55-70 months. The median OS difference of high gene vs. low gene expression groups ranged from 15-25 months. EHBP1 gene, involved in endocytic trafficking of transferrin into endosomes and GLUT4 into adipocytes, had the greatest difference in median OS between high and low expressions at 25 months (p= 2.16E-3). Finally, low expression of PPM2C compared to its high expression was significantly associated with &gt; 5 year survival (10.1% vs. 1.1%, p=0.001) and no recurrence in both training and validation sets (12.5% vs. 2.2%, p=0.04). PPM2C encodes for pyruvate dehydrogenase-phosphatase 1 that catalyzes reactivation of the alpha subunit of the E1 component of the pyruvate dehydrogenase complex. Pyruvate dehydrogenase complex in the active form transforms pyruvate from glycolysis to acetyl-CoA in the mitochondria. To evaluate whether similar findings are noted in other cancers, we also examined the TCGA data for breast, lung, colon cancer, and glioblastoma. PPM2C is amplified by 7% in invasive breast cancer, and leads to an overall worse survival (68.9 months vs. 129.5 months, p = 0.037).

Conclusion: Genes involved in cell metabolism, neurotransmitter functioning, and endocytic trafficking are highly predictive of outcome in high grade serous ovarian cancer. High PPM2C expression and gene amplification leads to worsening overall survival in ovarian and invasive breast cancer, respectively. These pathways likely reflect novel and important therapeutic targets.

Citation Format: Behrouz Zand, Cristina Ivan, Chad V. Pecot, Rajesha Rupaimoole, Heather J. Dalton, Justin Bottsford-Miller, Wei Hu, Alpa M. Nick, Anil K. Sood. Ten degrees of separation: novel genes affecting outcome in ovarian cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4024. doi:10.1158/1538-7445.AM2013-4024