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

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          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.

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          Most cited references 44

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          The Japanese guidelines for gastric cancer screening.

          Gastric cancer is the leading cause of death from cancer in Japan. In 2004, there were 50 562 deaths from gastric cancer; they accounted for 15.8% of the total number of cancer deaths. Since 1983, under the Health Service Law for the Aged, gastric cancer screening has been conducted nationwide for all residents aged 40 years and over. On the basis of the standardized method developed for the Japanese Guidelines for Cancer Screening, the efficacies of various methods for gastric cancer screening were evaluated and the guideline was developed. Four methods for gastric cancer screening were evaluated: photofluorography, endoscopy, serum pepsinogen testing and Helicobacter pylori antibody testing. On the basis of the analytic framework involving key questions, 1715 articles, published from January 1985 to February 2005, were selected using MEDLINE, the Japanese Medical Research Database and other methods. After the systematic literature review, 10 articles were identified as direct evidence and 49 articles as indirect evidence. The studies that evaluated mortality reduction from gastric cancer included five case-control and two cohort studies for radiographic screening. On the basis of the balance of benefits and harms, the recommendations for population-based and opportunistic screening were formulated. Gastric cancer screening using photofluorography was recommended for both screening programs. The other methods were not recommended for population-based screening due to insufficient evidence. The guideline for gastric cancer screening guideline was developed based on the previously established method. Gastric cancer screening using photofluorography is recommended for population-based and opportunistic screening in Japan.
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            HER2-positive gastric cancer

             Narikazu Boku (2013)
            Human epidermal growth factor receptor 2 (HER2) is involved in the pathogenesis and poor outcomes of several types of cancer, including advanced gastric and gastroesophageal junction cancer. Molecular-targeted drugs, such as trastuzumab, which prolong overall survival and progression-free survival in HER2-positive breast cancer, may also be beneficial in patients with HER2-positive gastric cancer. Several studies have examined this possibility, such as the Trastuzumab for Gastric Cancer trial. In this context, the first part of this review provides an update on our knowledge of HER2 in breast and gastric cancer, including the detection and prognostic relevance of HER2 in gastric cancer. The second part of the review discusses the results of pivotal clinical trials that examined the potential for using trastuzumab to treat this disease. This section also summarizes the trials that have been conducted or that are underway to determine the optimal uses of trastuzumab in gastric cancer, including its use as monotherapy and continuation beyond disease progression. The final section discusses the future prospects of other anti-HER2 drugs, including lapatinib, trastuzumab emtansine, and pertuzumab, for the treatment of HER2-positive gastric cancer. The introduction of trastuzumab led to the establishment of a new disease entity, “HER2-positive gastric cancer,” similar to HER2-positive breast cancer. It is expected that more anti-HER2 drugs will be developed and introduced into clinical practice to treat HER2-positive cancers, including gastric cancer.
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              A meta-analysis of gene expression-based biomarkers predicting outcome after tamoxifen treatment in breast cancer.

              To date, three molecular markers (ER, PR, and CYP2D6) have been used in clinical setting to predict the benefit of the anti-estrogen tamoxifen therapy. Our aim was to validate new biomarker candidates predicting response to tamoxifen treatment in breast cancer by evaluating these in a meta-analysis of available transcriptomic datasets with known treatment and follow-up. Biomarker candidates were identified in Pubmed and in the 2007-2012 ASCO and 2011-2012 SABCS abstracts. Breast cancer microarray datasets of endocrine therapy-treated patients were downloaded from GEO and EGA and RNAseq datasets from TCGA. Of the biomarker candidates, only those identified or already validated in a clinical cohort were included. Relapse-free survival (RFS) up to 5 years was used as endpoint in a ROC analysis in the GEO and RNAseq datasets. In the EGA dataset, Kaplan-Meier analysis was performed for overall survival. Statistical significance was set at p < 0.005. The transcriptomic datasets included 665 GEO-based and 1,208 EGA-based patient samples. All together 68 biomarker candidates were identified. Of these, the best performing genes were PGR (AUC = 0.64, p = 2.3E-07), MAPT (AUC = 0.62, p = 7.8E-05), and SLC7A5 (AUC = 0.62, p = 9.2E-05). Further genes significantly correlated to RFS include FOS, TP53, BTG2, HOXB7, DRG1, CXCL10, and TPM4. In the RNAseq dataset, only ERBB2, EDF1, and MAPK1 reached statistical significance. We evaluated tamoxifen-resistance genes in three independent platforms and identified PGR, MAPT, and SLC7A5 as the most promising prognostic biomarkers in tamoxifen treated patients.
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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                2 August 2016
                30 June 2016
                : 7
                : 31
                : 49322-49333
                Affiliations
                1 MTA-TTK Lendület Cancer Biomarker Research Group, Budapest, Hungary
                2 2nd Department of Pathology, Semmelweis University, Budapest, Hungary
                3 Max Delbrück Center for Molecular Medicine, Berlin, Germany
                4 Transgenic Oncogenesis and Genomics Section, Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
                5 Cancer Genetics and Genomics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Australia
                6 Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia
                7 Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Melbourne, Australia
                8 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary
                Author notes
                Correspondence to: Balázs Győrffy, gyorffy.balazs@ 123456ttk.mta.hu
                Article
                10337
                10.18632/oncotarget.10337
                5226511
                27384994
                Copyright: © 2016 Szász et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Categories
                Research Paper

                Oncology & Radiotherapy

                gastric cancer, survival, meta-analysis

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