Abstract LB-111: Elevated CXXC5 is associated with recurrence, poor overall survival and cell viability in endometrial cancer
Authors: Fedorko Alyssa , Chandramouli Gadisetti V.R. , Kim Hong Im , Shoji Yutaka , Challa Rusheeswar , Darcy Kathleen M. , Wang Guisong , Schink Julian , Conrads Thomas P. , Risinger John 
Published: July 2016

Endometrial cancer is the fourth most common cancer in women and the most prevalent gynecologic malignancy in the United States, however, there has been little improvement in treatment strategies. This problem will become more eminent in the future as the incidence and prevalence of this disease is increasing overall. As it did decades ago, determination of therapeutic modality still relies heavily on two subjective measures: surgical staging and pathological classification. Thus, new markers are needed to more objectively assess disease state and predict potential progression. We have used two independent datasets (Internal and TCGA) containing quantified measures of the transcriptome derived from both serous and endometrioid endometrial cancers to identify upregulated transcripts that are predictive of overall survival (OS) and/or disease-free survival (DFS). In initial analysis of our internal dataset we identified 114 transcripts at p&lt;0.005 that were associated with OS, DFS or both by COX regression analysis. We focused on those transcripts with elevated hazard ratios and determined whether these transcripts retained similar survival associations with the endometrial cancer samples in The Cancer Genome Atlas (TCGA) data set.

In this study we focused on the most impressive of the transcripts we have identified, CXXC5, which is an understudied gene. Elevated levels of CXXC5 demonstrated an impressive association with recurrence (p = 0.000009 in TCGA). We next determined that those TCGA cancers that are high CXXC5 expressors (upper quartile) also had worse OS and DFS as compared to those in the low expressor group. Finally, we verified CXXC5 overexpression as being predictive of recurrence by quantitative RT-PCR (p≤0.03) in an independent set of 80 endometrial cancers.

We examined several oncogenic phenotypes in two uterine serous cancer cell line models following shRNA mediated CXXC5 knockdown. CXXC5 expression was effectively knocked down in 4 of 5 lentiviral shRNAs targeting CXXC5 as compared to non-targeting controls and was confirmed for both the protein and RNA level. CXXC5 knockdown cells displayed a slower metabolic rate as measured by MTS assay, showed a dramatic (&gt;70%) reduction in colony formation and also had increased levels of caspase 3/7 activity. Overall, our results suggest that elevated CXXC5 levels promote cell viability in endometrial cancers overexpressing CXXC5. Thus, CXXC5 could serve not only as a predictive clinical marker for poor outcome disease, but also as a potential novel therapeutic target.

Citation Format: Alyssa Fedorko, Gadisetti V.R. Chandramouli, Hong Im Kim, Yutaka Shoji, Rusheeswar Challa, Kathleen M. Darcy, Guisong Wang, Julian Schink, Thomas P. Conrads, John Risinger. Elevated CXXC5 is associated with recurrence, poor overall survival and cell viability in endometrial cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-111.