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. 2016 Aug 2;7(31):49322-49333.
doi: 10.18632/oncotarget.10337.

Cross-validation of survival associated biomarkers in gastric cancer using transcriptomic data of 1,065 patients

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Cross-validation of survival associated biomarkers in gastric cancer using transcriptomic data of 1,065 patients

A Marcell Szász et al. Oncotarget. .

Abstract

Introduction: Multiple gene expression based prognostic biomarkers have been repeatedly identified in gastric carcinoma. However, without confirmation in an independent validation study, their clinical utility is limited. Our goal was to establish a robust database enabling the swift validation of previous and future gastric cancer survival biomarker candidates.

Results: The entire database incorporates 1,065 gastric carcinoma samples, gene expression data. Out of 29 established markers, higher expression of BECN1 (HR = 0.68, p = 1.5E-05), CASP3 (HR = 0.5, p = 6E-14), COX2 (HR = 0.72, p = 0.0013), CTGF (HR = 0.72, p = 0.00051), CTNNB1 (HR = 0.47, p = 4.3E-15), MET (HR = 0.63, p = 1.3E-05), and SIRT1 (HR = 0.64, p = 2.2E-07) correlated to longer OS. Higher expression of BIRC5 (HR = 1.45, p = 1E-04), CNTN1 (HR = 1.44, p = 3.5E- 05), EGFR (HR = 1.86, p = 8.5E-11), ERCC1 (HR = 1.36, p = 0.0012), HER2 (HR = 1.41, p = 0.00011), MMP2 (HR = 1.78, p = 2.6E-09), PFKB4 (HR = 1.56, p = 3.2E-07), SPHK1 (HR = 1.61, p = 3.1E-06), SP1 (HR = 1.45, p = 1.6E-05), TIMP1 (HR = 1.92, p = 2.2E- 10) and VEGF (HR = 1.53, p = 5.7E-06) were predictive for poor OS.

Materials and methods: We integrated samples of three major cancer research centers (Berlin, Bethesda and Melbourne datasets) and publicly available datasets with available follow-up data to form a single integrated database. Subsequently, we performed a literature search for prognostic markers in gastric carcinomas (PubMed, 2012-2015) and re-validated their findings predicting first progression (FP) and overall survival (OS) using uni- and multivariate Cox proportional hazards regression analysis.

Conclusions: The major advantage of our analysis is that we evaluated all genes in the same set of patients thereby making direct comparison of the markers feasible. The best performing genes include BIRC5, CASP3, CTNNB1, TIMP-1, MMP-2, SIRT, and VEGF.

Keywords: gastric cancer; meta-analysis; survival.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1. Database setup and clinical characteristics
List of datasets included in the database as well as basic clinical characteristics (A). Number of patients are given for TNM, because not all patients had these data available. Overall survival and time to first progression in all patients, (B) and effect of stage on overall survival (C).
Figure 2
Figure 2. Survival for a selected set of the best performing markers
Kaplan-Meier survival plots show that higher expression of CASP3, CTNNB1 and SIRT1 results in a better OS, while higher expression of BIRC5, TIMP-1 and HER2 lead to worse survival (A). Forest plots for CASP3, TIMP-1, and HER2 (B).
Figure 3
Figure 3. Expression change comparing normal and cancer tissue
All markers ranked by the fold change (A), MMP-2 was the only gene down regulated at p < 0.01 and FC < 0.66 (B). Six genes had an expression increase over 1.5 fold with a p < 0.01 (C). The normalized expression values are shown for each gene. p: Mann-Whitney p value comparing normal and tumor samples. Red bar: 95% confidence interval.

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