Abstract 658: CRABP2 - a novel biomarker for high risk endometrial cancer
Authors: Egan Donagh , Moran Bruce , Wilkinson Michael , Gallagher William , Matias-Guiu Xavier , Kolch Walter , LeRoux Carel , Brennan Donal 
Published: July 2021

Introduction: The incidence of endometrial cancer (EC) is rising - a consequence of the current obesity epidemic. An improved understanding of obesity-induced EC is needed to manage this growing cohort of patients. Here-in we present Cellular Retinoic Acid Binding Protein 2 (CRABP2), which was identified as an obesity-related gene in the BDII/Han rat spontaneous EC model, as a novel biomarker in high-risk EC.

Methods:BDII/Han rats were fed either a high (N=12) or low calorie (N=7) diet for 15 months. RNA-seq, - differential gene expression and gene set enrichment analysis (GSEA) were performed on endometrial tumors from both groups. The association between CRABP2 mRNA expression and standard clinico-pathological features was examined in human EC using the TCGA. Following dichotomization of patients based on their CRABP2 mRNA expression using regression tree analysis, univariate and multivariate Cox regression survival analyses were performed. Differential gene expression analysis and GSEA were performed on human tumors stratified according to CRABP2 expression levels. In-silico findings were validated using immunohistochemistry (IHC) assessing CRABP2 expression in normal endometrium, primary and metastatic endometrial carcinoma.

Results:Weight gain in high fat diet (HFD) rats was double that of normal chow diet rats (50 g vs. 25 g). The incidence of cancer was similar in both groups (4/7-57% vs. 4/12-33%; p=0.37). 368 differentially expressed genes (DEGs) were identified between both groups. CRABP2 was upregulated in tumors from the HFD group. Regression tree analysis identified 60 (11%) tumors in the TCGA with increased CRABP2 mRNA expression. Increased CRABP2 expression was associated with serous EC (p&lt;0.001), grade 3 (p&lt;0.001) and advanced stage (p=0.015). Univariate Cox regression analysis revealed that high CRABP2 expression is associated with reduced overall survival (HR=2.67, 95% CI 1.64-4.33, p&lt;0.001). This remained true following multivariate cox regression analysis in which age, histological type, stage and grade were confounded for (HR=2.06, 95% CI 1.24-3.41, p=0.004). 224 DEGs were identified between CRABP2 high (N=60) and low (N=468) tumors in the TCGA. GSEA analysis revealed an enrichment of pathways involved in developmental biology and embryonic stem cell-like gene expression signatures in the CRABP2-high cohort. IHC confirmed increased expression of cytoplasmic CRABP2 in EC compared to normal endometrium. CRABP2 expression was significantly increased in serous compared to endometrioid cancer (p&lt;0.05) and a comparison between primary and metastatic serous carcinoma demonstrated increased expression in metastatic cases.

Conclusion: A HFD increased CRABP2 expression in rat EC. In humans, increased expression of CRABP2 is associated with high-risk EC. Transcriptomic analysis and validation using IHC suggests that CRABP2 and retinoic acid signalling may be an important therapeutic target in advanced EC.

Citation Format: Donagh Egan, Bruce Moran, Michael Wilkinson, William Gallagher, Xavier Matias-Guiu, Walter Kolch, Carel LeRoux, Donal Brennan. CRABP2 - a novel biomarker for high risk endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 658.