Abstract 4034: An integrated analysis of the eph/ephrin family: implications in endometrial cancer.
Authors: Dalton Heather J. , Ivan Cristina , Pecot Chad V. , Rupamaiole Rajesha , Zand Behrouz , Bottsford-Miller Justin , Hu Wei , Nick Alpa M. , Coleman Robert L. , Sood Anil K. 
Published: August 2014

Objective: Members of the Eph/Ephrin family are known to play seminal roles in cancer growth and metastasis in many solid tumors; however, a comprehensive analysis has not been carried out. We analyzed the clinical relevance of all Eph/Ephrin family members in endometrial cancer.

Methods: Level 3 data from The Cancer Genome Atlas (TCGA) was utilized to assess the clinical significance of all 14 Eph receptors available in the database (EphA1-8, EphA10, EphB1-4, and EphB6), as well as EphrinA1-A5 and EphrinB1-B3. We examined gene methylation status and copy number changes in these tumors. Clinical information extracted included age, tumor histology, tumor grade, stage, estrogen(ER)/progesterone(PR) receptor status, and overall survival.

Results: A total of 320 samples were available for analysis. Increased EphA2, EphA4, EphB1, and EphB2 expression was significantly correlated with poorer overall survival (p=0.03, p=0.04, p=0.01, and p=0.008, respectively) and lack of ER and PR expression (r=-0.34, p=2.25e−6; r-0.24, p=0.0007; r=-0.22, p=0.002; r=-0.46, p=2.38e−11, respectively). Compared to endometrioid histology, serous histology was associated with increased expression of EphA2 (p&lt;0.0001), EphA4 (p&lt;0.0002), EphB1 (p&lt;0.0001), EphB2 (p&lt;0.0001), and EphrinA3 (p=0.04). Grade 3 tumor samples had increased expression of EphA2 (p&lt;0.03), EphA4 (p&lt;0.006), EphB1 (p&lt;0.0001), EphB2 (p&lt;0.0001), and EphrinA3 (p=0.04) compared to lower grade samples. EphA2, EphB1, and EphB2 expression was higher in samples from patients with advanced stage (FIGO Stage IIIA-IVB) compared to those with early stage disease (p=0.008, p=0.0183, and p&lt;0.001, respectively). Patients age &gt; 63 years had greater tumoral expression of EphA4 (p&lt;0.0001), EphB2 (p=0.001), and EphrinA3 (p=0.03). Increased copy number correlated with EphB2 (r=0.41, p=0.001) and EphrinA3 (r=0.23, p=0.02) expression, but was not correlated with other Eph or Ephrin gene expression. Gene methylation inversely correlated with EphA2, EphA4, EphB1, EphB2, EphrinA3, and EphrinA5 receptor expression (r&lt;-0.22, p&lt;0.0001; r&lt;-0.26, p&lt;0.0002; r&lt;-0.23, p&lt;0.0006; r&lt;-0.21, p&lt;0.003; r&lt;-0.2, p&lt;0.01; r&lt;-0.2, p&lt;0.01, respectively). In patients with advanced stage expression of EphrinA3 and EphrinA5 was associated with poorer OS (p=0.002 and p=0.012). In a multivariate analysis, stage and Eph expression were the strongest independent predictors of poor survival, of which, EphA4 was the most significant (p=0.0024). In further support of the significance of EphA4, increased expression of its ligands EphrinA3 and EprhinA5 correlated with poorer OS.

Conclusions: Concordant with emerging roles for the Eph receptor and Eprhins in driving malignant biology, increased EphA2, EphA4, EphB1, and EphB2 expression, as well as EphrinA3 and EphrinA5 expression, is predictive of poor patient outcome and constitutes attractive targets for biological therapies.

Citation Format: Heather J. Dalton, Cristina Ivan, Chad V. Pecot, Rajesha Rupamaiole, Behrouz Zand, Justin Bottsford-Miller, Wei Hu, Alpa M. Nick, Robert L. Coleman, Anil K. Sood. An integrated analysis of the eph/ephrin family: implications in endometrial 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 4034. doi:10.1158/1538-7445.AM2013-4034