Patrick Sven Plum1,2,3,4, Heike Löser5,6, Thomas Zander7,8, Ahlem Essakly6, Christiane J Bruns9,7, Axel M Hillmer6, Hakan Alakus9,7, Wolfgang Schröder9,7, Reinhard Büttner6, Florian Gebauer9,7, Alexander Quaas5,7,6. 1. Department of General, Visceral, Cancer, and Transplantation Surgery, University of Cologne, Faculty of Medicine, and University Hospital Cologne, Kerpener Straße 62, 50937, Cologne, Germany. Patrick.plum@uk-koeln.de. 2. Gastrointestinal Cancer Group Cologne (GCGC), Cologne, Germany. Patrick.plum@uk-koeln.de. 3. Else Kröner Forschungskolleg Cologne "Clonal Evolution in Cancer", Cologne, Germany. Patrick.plum@uk-koeln.de. 4. Centre for Integrated Oncology (CIO), Cologne Bonn, Cologne, Germany. Patrick.plum@uk-koeln.de. 5. Gastrointestinal Cancer Group Cologne (GCGC), Cologne, Germany. 6. Institute of Pathology, University of Cologne, Faculty of Medicine, and University Hospital Cologne, Kerpener Straße 62, 50937, Cologne, Germany. 7. Centre for Integrated Oncology (CIO), Cologne Bonn, Cologne, Germany. 8. Department of Internal Medicine I, University of Cologne, Faculty of Medicine, and University Hospital Cologne, Kerpener Straße 62, 50937, Cologne, Germany. 9. Department of General, Visceral, Cancer, and Transplantation Surgery, University of Cologne, Faculty of Medicine, and University Hospital Cologne, Kerpener Straße 62, 50937, Cologne, Germany.
Abstract
PURPOSE: Driver mutations are typically absent in esophageal adenocarcinoma (EAC). Mostly, oncogenes are amplified as driving molecular events (including GATA6-amplification in 14% of cases). However, only little is known about its biological function and clinical relevance. METHODS: We examined a large number of EAC (n = 496) for their GATA6 amplification by fluorescence in situ hybridization (FISH) analyzing both primary resected (n = 219) and neoadjuvant treated EAC (n = 277). Results were correlated to clinicopathological data and known mutations/amplifications in our EAC-cohort. RESULTS: GATA6 amplification was detectable in 49 (9.9%) EACs of our cohort. We observed an enrichment of GATA6-positive tumors among patients after neoadjuvant treatment (12,3% amplified tumors versus 6,8% in the primary resected group; p = 0.044). Additionally, there was a simultaneous amplification of PIK3CA and GATA6 (p < 0.001) not detectable when analyzing other genes such as EGFR, ERBB2, KRAS or MDM2. Although we did not identify a survival difference depending on GATA6 in the entire cohort (p = 0.212), GATA6 amplification was associated with prolonged overall survival among patients with primary surgery (median overall-survival 121.1 vs. 41.4 months, p = 0.032). Multivariate cox-regression analysis did not confirm GATA6 as an independent prognostic marker, neither in the entire cohort (p = 0.210), nor in the subgroup with (p = 0.655) or without pretreatment (p = 0.961). CONCLUSIONS: Our study investigates the relevance of GATA6 amplification on a large tumor collective, which includes primary resected tumors and the clinically relevant group of neoadjuvant treated EACs. Especially in the pretreated group, we found an accumulation of GATA6-amplified tumors (12.3%) and a frequent co-amplification of PIK3CA. Our data suggest an increased resistance to radio-chemotherapy in GATA6-amplified tumors.
PURPOSE: Driver mutations are typically absent in esophageal adenocarcinoma (EAC). Mostly, oncogenes are amplified as driving molecular events (including GATA6-amplification in 14% of cases). However, only little is known about its biological function and clinical relevance. METHODS: We examined a large number of EAC (n = 496) for their GATA6 amplification by fluorescence in situ hybridization (FISH) analyzing both primary resected (n = 219) and neoadjuvant treated EAC (n = 277). Results were correlated to clinicopathological data and known mutations/amplifications in our EAC-cohort. RESULTS:GATA6 amplification was detectable in 49 (9.9%) EACs of our cohort. We observed an enrichment of GATA6-positive tumors among patients after neoadjuvant treatment (12,3% amplified tumors versus 6,8% in the primary resected group; p = 0.044). Additionally, there was a simultaneous amplification of PIK3CA and GATA6 (p < 0.001) not detectable when analyzing other genes such as EGFR, ERBB2, KRAS or MDM2. Although we did not identify a survival difference depending on GATA6 in the entire cohort (p = 0.212), GATA6 amplification was associated with prolonged overall survival among patients with primary surgery (median overall-survival 121.1 vs. 41.4 months, p = 0.032). Multivariate cox-regression analysis did not confirm GATA6 as an independent prognostic marker, neither in the entire cohort (p = 0.210), nor in the subgroup with (p = 0.655) or without pretreatment (p = 0.961). CONCLUSIONS: Our study investigates the relevance of GATA6 amplification on a large tumor collective, which includes primary resected tumors and the clinically relevant group of neoadjuvant treated EACs. Especially in the pretreated group, we found an accumulation of GATA6-amplified tumors (12.3%) and a frequent co-amplification of PIK3CA. Our data suggest an increased resistance to radio-chemotherapy in GATA6-amplified tumors.
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