Karsten Kleo1, Vladimir M Jovanovic2, Alexander Arndold1, Annika Lehmann1, Hedwig Lammert1, Erika Berg1, Hannah Harloff3, Christoph Treese3,4,5, Michael Hummel1, Severin Daum6,7. 1. Institute of Pathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Chariteplatz 1, 10117, Berlin, Germany. 2. Institute of Informatics, Bioinformatics Solution Center, Freie Universität (FU), Takustr. 9, 14195, Berlin, Germany. 3. Medical Department, Division of Gastroenterology, Infectious Diseases and Rheumatology, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200, Berlin, Germany. 4. Experimental and Clinical Research Center, Charité University Medicine, Berlin and Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Chariteplatz 1, 10117, Berlin, Germany. 5. Core Facility Genomics, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany. 6. Medical Department, Division of Gastroenterology, Infectious Diseases and Rheumatology, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200, Berlin, Germany. severin.daum@charite.de. 7. Core Facility Genomics, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany. severin.daum@charite.de.
Abstract
OBJECTIVES: Perioperative chemo-(radio-) therapy is the accepted standard in European patients with locally advanced adenocarcinoma of the esophagogastric junction or stomach (AEG/AS). However, 30-85% of patients do not respond to this treatment. The aim of our study was the identification of predictive biomarkers in pre-therapeutic endoscopic tumor biopsies from patients with histopathologic response (Becker-1) versus non-response (Becker-2/3) to preoperative chemotherapy. METHODS: Formalin-fixed paraffin-embedded biopsies from 36 Caucasian patients (Becker-1 n = 11, Becker-2 n = 7, Becker-3 n = 18) with AEG/AS, taken prior to neoadjuvant chemotherapy were selected. For RNA expression analysis, we employed the NanoString nCounter System. To identify genomic alterations like single nucleotide variants (SNV), copy number variation (CNV) and fusion events, we used Illumina TST170 gene panel. For HER2 and FGFR2 protein expression, immunostaining was performed. Furthermore, we analyzed the microsatellite instability (MSI) and Epstein-Barr virus (EBV) infection status by EBER in situ hybridization. RESULTS: Heat map and principal component analyses showed no clustering by means of gene expression according to regression grade. Concerning two recently proposed predictive markers, our data showed equal distribution for MSI (Becker-1: 2; Becker-2: 1; Becker-3: 3; out of 29 tested) and EBV infection was rare (1/32). We could not reveal discriminating target genes concerning SNV, but found a higher mutational burden in non-responders versus responders and fusion (in 6/14) and CNV events (in 5/14) exclusively in Becker-3. CONCLUSIONS: Although we could not identify discriminating target genes, our data suggest that molecular alterations are in general more prevalent in patients with AEG/AS belonging to the non-responding Becker group 3.
OBJECTIVES: Perioperative chemo-(radio-) therapy is the accepted standard in European patients with locally advanced adenocarcinoma of the esophagogastric junction or stomach (AEG/AS). However, 30-85% of patients do not respond to this treatment. The aim of our study was the identification of predictive biomarkers in pre-therapeutic endoscopic tumor biopsies from patients with histopathologic response (Becker-1) versus non-response (Becker-2/3) to preoperative chemotherapy. METHODS: Formalin-fixed paraffin-embedded biopsies from 36 Caucasian patients (Becker-1 n = 11, Becker-2 n = 7, Becker-3 n = 18) with AEG/AS, taken prior to neoadjuvant chemotherapy were selected. For RNA expression analysis, we employed the NanoString nCounter System. To identify genomic alterations like single nucleotide variants (SNV), copy number variation (CNV) and fusion events, we used Illumina TST170 gene panel. For HER2 and FGFR2 protein expression, immunostaining was performed. Furthermore, we analyzed the microsatellite instability (MSI) and Epstein-Barr virus (EBV) infection status by EBER in situ hybridization. RESULTS: Heat map and principal component analyses showed no clustering by means of gene expression according to regression grade. Concerning two recently proposed predictive markers, our data showed equal distribution for MSI (Becker-1: 2; Becker-2: 1; Becker-3: 3; out of 29 tested) and EBV infection was rare (1/32). We could not reveal discriminating target genes concerning SNV, but found a higher mutational burden in non-responders versus responders and fusion (in 6/14) and CNV events (in 5/14) exclusively in Becker-3. CONCLUSIONS: Although we could not identify discriminating target genes, our data suggest that molecular alterations are in general more prevalent in patients with AEG/AS belonging to the non-responding Becker group 3.
Keywords:
Gastric and esophagogastric adenocarcinoma; Histopathological response according to Becker score; Perioperative chemotherapy; Predictive biomarker in pre-therapeutic biopsies; Single nucleotide variants (SNV); copy number variations (CNV); gene expression
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