Molekulare Charakterisierung von Cholangiokarzinomen mit Fokus auf DNA Schadensreparaturgene in einem onkologischen Spitzenzentrum

Background: Aim of this work was the molecular characterisation of a cohort of cholangiocarcinomas (CCC) with a focus on genomic alterations of DNA damage repair (DDR) genes. Methods: This work presents a retrospective analysis of the clinical course and mutation status of patients with locally advanced or metastatic CCC treated at the West German Tumour Centre of Essen University Hospital. All information was retrieved from the hospital information system of the clinic. Microsatellite instability (MSI)/ DNA mismatch repair (MMR) status was determined by immunohistochemistry and DNA sequencing. Gene variants were assessed using two targeted DNA-based assays (MAPK-TRON customized NGS panel, 47 genes; AmoyDx HRD Focus panel, 32 genes) and an RNA fusion assay (FusionPlex CTL panel [Archer]). Time in first palliative regime till disease progression (Time on Treatment=ToT), overall survival (OS) and other secondary clinical endpoints were analysed statistically and using the long-rank test with mutation status and treatment data. Results: The cohort of the present study comprises 113 patients. All patients received the MAPK-TRON NGS (next generation sequencing) panel, 81 additionally the HRD (homologous recombination deficiency) focus panel (71.7%). In 59 patients, the MMR status (mismatch repair, 52.2 %) was examined. 33 samples were analysed with the RNA fusion assay (29.2 %). TP53 (33/113, 29.2%), KRAS (25/113, 22.1%), IDH1/2 (18/113, 16%), PIK3CA (8/113, 7%) and BRAF (6/113, 5.3%) were identified as the most frequently mutated genes. DDR-mutations were detected in 13 patients (13/113, 11.5%). The patients with DDR mutations showed a weak but coherent benefit in all primary endpoints (OS, ToT, OS after platinum therapy). Conclusions: DDR-deficient CCC patients showed a potential advantage in OS and ToT and represent a potential subgroup that benefits from platinum-containing treatment strategies.Background: Aim of this work was the molecular characterisation of a cohort of cholangiocarcinomas (CCC) with a focus on genomic alterations of DNA damage repair (DDR) genes. Methods: This work presents a retrospective analysis of the clinical course and mutation status of patients with locally advanced or metastatic CCC treated at the West German Tumour Centre of Essen University Hospital. All information was retrieved from the hospital information system of the clinic. Microsatellite instability (MSI)/ DNA mismatch repair (MMR) status was determined by immunohistochemistry and DNA sequencing. Gene variants were assessed using two targeted DNA-based assays (MAPK-TRON customized NGS panel, 47 genes; AmoyDx HRD Focus panel, 32 genes) and an RNA fusion assay (FusionPlex CTL panel [Archer]). Time in first palliative regime till disease progression (Time on Treatment=ToT), overall survival (OS) and other secondary clinical endpoints were analysed statistically and using the long-rank test with mutation status and treatment data. Results: The cohort of the present study comprises 113 patients. All patients received the MAPK-TRON NGS (next generation sequencing) panel, 81 additionally the HRD (homologous recombination deficiency) focus panel (71.7%). In 59 patients, the MMR status (mismatch repair, 52.2 %) was examined. 33 samples were analysed with the RNA fusion assay (29.2 %). TP53 (33/113, 29.2%), KRAS (25/113, 22.1%), IDH1/2 (18/113, 16%), PIK3CA (8/113, 7%) and BRAF (6/113, 5.3%) were identified as the most frequently mutated genes. DDR-mutations were detected in 13 patients (13/113, 11.5%). The patients with DDR mutations showed a weak but coherent benefit in all primary endpoints (OS, ToT, OS after platinum therapy). Conclusions: DDR-deficient CCC patients showed a potential advantage in OS and ToT and represent a potential subgroup that benefits from platinum-containing treatment strategies.

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