Abstract 3806: Integrative omics analysis in gastric cancer reveals SLC7A5 functional related to DNA mismatch repair system as a potential therapeutic biomarker in GC

Abstract

Abstract Background: Metastasis is a major cause leading to high mortality rate and poor prognosis in Gastric Cancer (GC) patients. Our previous studies showed that SLC7A5 is an amino acid transporter gene meditated by a pivotal post-transcriptional tumor suppressor mir-126 and associated with tumor metastasis in GC. Purpose: (a) to further determine the SLC7A5 functional mechanisms in GC by involving more bio-omics data such as DNA methylation, copy number variation (CNV) and mRNA expression; b) to study the association of SLC7A5 bio-omics data with the clinicopathologic features, prognosis and subtypes in GC patients. Methods: We intensively performed the genome-wide association study for bio-omics data of GC patients available from The Cancer Genome Atlas (TCGA, n=421) and Gene Expression Omnibus published studies (GEO, GSE13911, n=69, GSE15459, n=209). We did Kaplan-Meier survival analysis and univariate Cox regression model analyses in SLC7A5 mRNA expression from curated database (http://www.kmplot.com) with 882 GC patients for overall survival and 646 GC patients for progression free survival analysis. Results: CNV of SLC7A5 is positively correlated with mRNA expression (p=3.18e-07), which suggests that SLC7A5 is potentially a target driver gene for GC. Further integrative analysis identified two important methylation probes in promotor region (TSS200 position) negatively correlated with mRNA expression of SLC7A5 (p=1.03e-3). In addition, the aberrant high methylation and expression of SLC7A5, which were significantly higher than the corresponding nonmalignant tissues, were identified in a subset of gastric cancer patients. Interestingly, SLC7A5 showed statistically significant correlation with the mismatch repair-deficient phenotype in sporadic microsatellite instability gastric cancer (p=2.12e-5). Data mining from two independent datasets of GEO validated SLC7A5 is positively correlated with DNA mismatch repair genes MLH1, BRCA1 and BRCA2. And further Gene Ontology (GO) pathway analysis suggested that SLC7A5 and DNA mismatch repair genes (MMR) together shared the same metabolic processes. Importantly, the overall survival from 882 GC patients and progression free survival analysis from 646 GC patients showed SLC7A5 high expression is associated with poor prognosis tumorigenesis, which demonstrated that SLC7A5 is a potential independent biomarker for GC. Conclusion: We found SLC7A5 has positive interaction with DNA mismatch genes through database mining, which result in microsatellite instability phenotype in GC patients. We also found SLC7A5 over expression is associated with poor prognosis and potentially an pivotal therapeutic target in GC. Note: This abstract was not presented at the meeting. Citation Format: Yunyun Zhou, Xuehua Chen, Zhenggang Zhu, Junqing Wang. Integrative omics analysis in gastric cancer reveals SLC7A5 functional related to DNA mismatch repair system as a potential therapeutic biomarker in GC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3806. doi:10.1158/1538-7445.AM2017-3806