Damian Stichel1,2, Daniel Schrimpf1,2, Philipp Sievers1,2, Annekathrin Reinhardt1,2, Abigail K Suwala1,2, Martin Sill3,4, David E Reuss1,2, Andrey Korshunov1,2,3, Belén M Casalini1,2, Alexander C Sommerkamp3,5,6, Jonas Ecker3,7,8, Florian Selt3,7,8, Dominik Sturm3,5,7, Astrid Gnekow9, Arend Koch10,11, Michèle Simon12, Pablo Hernáiz Driever12, Ulrich Schüller13,14,15, David Capper10,11, Cornelis M van Tilburg3,7,8, Olaf Witt3,7,8, Till Milde3,7,8, Stefan M Pfister3,4,7, David T W Jones3,5, Andreas von Deimling1,2, Felix Sahm1,2,3, Annika K Wefers1,2,3,13,14,15. 1. Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany. 2. Clinical Cooperation Unit Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. 3. Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany. 4. Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. 5. Pediatric Glioma Research Group, German Cancer Research Center (DKFZ), Heidelberg, Germany. 6. Faculty of Biosciences, Heidelberg University, Heidelberg, Germany. 7. Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, Heidelberg University Hospital, Heidelberg, Germany. 8. Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany. 9. Swabian Children's Cancer Center, University Hospital Augsburg, Augsburg, Germany. 10. Department of Neuropathology, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany. 11. German Cancer Consortium (DKTK, Partner Site Berlin, German Cancer Research Center (DKFZ, Heidelberg, Germany. 12. Department of Pediatric Oncology/Hematology and Stem Cell Transplantation, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany. 13. Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 14. Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 15. Research Institute Children's Cancer Center Hamburg, Hamburg, Germany.
Abstract
AIMS: KIAA1549-BRAF fusions occur in certain brain tumours and provide druggable targets due to a constitutive activation of the MAP-kinase pathway. We introduce workflows for calling the KIAA1549-BRAF fusion from DNA methylation array-derived copy number as well as DNA panel sequencing data. METHODS: Copy number profiles were analysed by automated screening and visual verification of a tandem duplication on chromosome 7q34, indicative of the KIAA1549-BRAF fusion. Pilocytic astrocytomas of the ICGC cohort with known fusion status were used for validation. KIAA1549-BRAF fusions were called from DNA panel sequencing data using the fusion callers Manta, Arriba with modified filtering criteria and deFuse. We screened DNA methylation and panel sequencing data of 7790 specimens from brain tumour and sarcoma entities. RESULTS: We identified the fusion in 337 brain tumours with both DNA methylation and panel sequencing data. Among these, we detected the fusion from copy number data in 84% and from DNA panel sequencing data in more than 90% using Arriba with modified filters. While in 74% the KIAA1549-BRAF fusion was detected from both methylation array-derived copy number and panel sequencing data, in 9% it was detected from copy number data only and in 16% from panel data only. The fusion was almost exclusively found in pilocytic astrocytomas, diffuse leptomeningeal glioneuronal tumours and high-grade astrocytomas with piloid features. CONCLUSIONS: The KIAA1549-BRAF fusion can be reliably detected from either DNA methylation array or DNA panel data. The use of both methods is recommended for the most sensitive detection of this diagnostically and therapeutically important marker.
AIMS: KIAA1549-BRAF fusions occur in certain brain tumours and provide druggable targets due to a constitutive activation of the MAP-kinase pathway. We introduce workflows for calling the KIAA1549-BRAF fusion from DNA methylation array-derived copy number as well as DNA panel sequencing data. METHODS: Copy number profiles were analysed by automated screening and visual verification of a tandem duplication on chromosome 7q34, indicative of the KIAA1549-BRAF fusion. Pilocytic astrocytomas of the ICGC cohort with known fusion status were used for validation. KIAA1549-BRAF fusions were called from DNA panel sequencing data using the fusion callers Manta, Arriba with modified filtering criteria and deFuse. We screened DNA methylation and panel sequencing data of 7790 specimens from brain tumour and sarcoma entities. RESULTS: We identified the fusion in 337 brain tumours with both DNA methylation and panel sequencing data. Among these, we detected the fusion from copy number data in 84% and from DNA panel sequencing data in more than 90% using Arriba with modified filters. While in 74% the KIAA1549-BRAF fusion was detected from both methylation array-derived copy number and panel sequencing data, in 9% it was detected from copy number data only and in 16% from panel data only. The fusion was almost exclusively found in pilocytic astrocytomas, diffuse leptomeningeal glioneuronal tumours and high-grade astrocytomas with piloid features. CONCLUSIONS: The KIAA1549-BRAF fusion can be reliably detected from either DNA methylation array or DNA panel data. The use of both methods is recommended for the most sensitive detection of this diagnostically and therapeutically important marker.
Authors: Till Milde; Fausto J Rodriguez; Jill S Barnholtz-Sloan; Nirav Patil; Charles G Eberhart; David H Gutmann Journal: Neuro Oncol Date: 2021-10-01 Impact factor: 13.029