Abstract 3879: Clinicopathological significance of key regulatory genes modulating the NFK-β pathway in Middle Eastern epithelial ovarian carcinoma
Authors: Zeenath Jehan, Prashant Bavi, Jehad Abubakr, Maqbool Ahmed, Mehar Sultana, Fouad Al-Dayel, Samir Ghourab, Shahab Uddin Uddin, Khawla S. Al-Kuraya
Journal: Cancer Research (2011)

Abstract NF-κβ signaling contributes to pathogenesis of several solid epithelial tumors including ovarian cancers. Activation of NF-κβ pathway leads to transcriptional activation of genes associated with cell proliferation, angiogenesis, metastasis, tumor promotion, inflammation and suppression of apoptosis. CARD10 and A20 genes are known positive and negative regulators of the NF-κβ activation pathway. CARD10 is an enzyme that is encoded by the CARD10 gene and it associates with IKK complex resulting in NF-κB activation. In this study we initially investigated the functional activation of NF-κβ pathway by examining the protein expression of NF-κB and phospho NF-κβ. Considering the potential therapeutic utility of targeting key modulators of NF-κβ, we studied CARD10 copy number variations of Card10 and A20 gene(A20 deletions) by FISH(Flourescent insitu hybridization) and the expressions of CARD10 and A20 protein by immunohistochemistry in tissue microarray cohort of 156 Middle Eastern epithelial ovarian carcinomas(EOCs). Using immunohistochemistry overexpression of NF-κβ, phospho NF-κβ and CARD10 was found in 18.7%, 17.2 % and 46.7% respectively. A20 inactivation, defined as reduced or complete loss of protein expression by IHC was observed in 23.8% of EOC samples. Surprisingly CARD10 amplification was observed in only 3.6% of samples suggesting the role of other alternate mechanism for overexpression of CARD10 protein. EOC subset with CARD10 overexpression showed an aggressive phenotype characterized by poor differentiation (p=0.0280), older age (p=0.0660), expression of anti-apoptotic markers BCLXL(p&amp;lt;0.0001)and XIAP(p=0.0294). Although CARD10 expression did not show any association with NF-κβ a significant association was observed with phospho NF-κβ (p=0.0027). Of the markers studied by Kaplan Meier survival analysis CARD10 protein expression (p=0.0018) and phospho p65 protein expression (p=0.0002) showed a poor progression free survival. In the multivariate analysis using Cox Proportional Hazard model for multiple factors like age, FIGO stage, grade, CARD10 and phospho p-65 expression, the relative risk was 1.72 for high CARD10 expression (95% CI 1.02-2.88); (p = 0.0401) and 2.16 for AJCC stage IV (95% CI 1.13-3.95; p=0.0210). Thus, only CARD-10 overexpression was an independent prognostic marker for poor survival in multivariate analysis. Our study highlights for the first time the role of CARD10 protein overexpression as a novel mechanism for NF-κβ activation, and demonstrates clinico-pathological significance of CARD10 and A20 alterations in Middle Eastern EOC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3879. doi:10.1158/1538-7445.AM2011-3879