Primary intracranial spindle cell sarcoma with rhabdomyosarcoma-like features share a highly distinct methylation profile and DICER1 mutations
Por:
Koelsche C, Mynarek M, Schrimpf D, Bertero L, Serrano J, Sahm F, Reuss DE, Hou Y, Baumhoer D, Vokuhl C, Flucke U, Petersen I, Brück W, Rutkowski S, Zambrano SC, Garcia Leon JL, Diaz Coronado RY, Gessler M, Tirado OM, Mora J, Alonso J, Garcia Del Muro X, Esteller M, Sturm D, Ecker J, Milde T, Pfister SM, Korshunov A, Snuderl M, Mechtersheimer G, Schüller U, Jones DTW and von Deimling A
Publicada:
1 ago 2018
Ahead of Print:
7 jun 2018
Resumen:
Patients with DICER1 predisposition syndrome have an increased risk to develop pleuropulmonary blastoma, cystic nephroma, embryonal rhabdomyosarcoma, and several other rare tumor entities. In this study, we identified 22 primary intracranial sarcomas, including 18 in pediatric patients, with a distinct methylation signature detected by array-based DNA-methylation profiling. In addition, two uterine rhabdomyosarcomas sharing identical features were identified. Gene panel sequencing of the 22 intracranial sarcomas revealed the almost unifying feature of DICER1 hotspot mutations (21/22; 95%) and a high frequency of co-occurring TP53 mutations (12/22; 55%). In addition, 17/22 (77%) sarcomas exhibited alterations in the mitogen-activated protein kinase pathway, most frequently affecting the mutational hotspots of KRAS (8/22; 36%) and mutations or deletions of NF1 (7/22; 32%), followed by mutations of FGFR4 (2/22; 9%), NRAS (2/22; 9%), and amplification of EGFR (1/22; 5%). A germline DICER1 mutation was detected in two of five cases with constitutional DNA available. Notably, none of the patients showed evidence of a cancer-related syndrome at the time of diagnosis. In contrast to the genetic findings, the morphological features of these tumors were less distinctive, although rhabdomyoblasts or rhabdomyoblast-like cells could retrospectively be detected in all cases. The identified combination of genetic events indicates a relationship between the intracranial tumors analyzed and DICER1 predisposition syndrome-associated sarcomas such as embryonal rhabdomyosarcoma or the recently described group of anaplastic sarcomas of the kidney. However, the intracranial tumors in our series were initially interpreted to represent various tumor types, but rhabdomyosarcoma was not among the typical differential diagnoses considered. Given the rarity of intracranial sarcomas, this molecularly clearly defined group comprises a considerable fraction thereof. We therefore propose the designation "spindle cell sarcoma with rhabdomyosarcoma-like features, DICER1 mutant" for this intriguing group.
Filiaciones:
Koelsche C:
Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany
Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
Department of General Pathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
Mynarek M:
Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Schrimpf D:
Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany
Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
Bertero L:
Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany
Pathology Unit, Department of Medical Sciences, University of Turin, Turin, Italy
Serrano J:
Department of Pathology, New York University School of Medicine, New York, USA
Sahm F:
Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany
Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
Reuss DE:
Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany
Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
Hou Y:
Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany
Baumhoer D:
Bone Tumour Reference Centre, Institute of Pathology, Basel University Hospital, Basel, Switzerland
Vokuhl C:
Department of Pediatric Pathology, University Hospital of Schleswig-Holstein, Kiel, Germany
Flucke U:
Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands
Petersen I:
Institute of Pathology, SRH Poliklinik Gera GmbH, Gera, Germany
Brück W:
Institute of Neuropathology, University Medical Center, Göttingen, Germany
Rutkowski S:
Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Zambrano SC:
Department of Pathology, Instituto Nacional de Enfermedades Neoplásicas (INEN), Lima, Peru
Garcia Leon JL:
Pediatric Oncology Unit, Clínica Anglo Americana, Lima, Peru
Pediatric Oncology Unit, Clínica Delgado, Lima, Peru
Department of Pediatric Oncology, Instituto Nacional de Enfermedades Neoplásicas (INEN), Lima, Peru
Diaz Coronado RY:
Department of Pediatric Oncology, Instituto Nacional de Enfermedades Neoplásicas (INEN), Lima, Peru
Gessler M:
Comprehensive Cancer Center Mainfranken, Würzburg University, Würzburg, Germany
Theodor-Boveri-Institute/Biocenter, Developmental Biochemistry, Würzburg University, Würzburg, Germany
Tirado OM:
Molecular Oncology Lab, Sarcoma Research Group, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain
Mora J:
Department of Pediatric Onco-Hematology and Developmental Tumor Biology Laboratory, Hospital Sant Joan de Déu, Barcelona, Catalonia, Spain
Alonso J:
Pediatric Solid Tumor Laboratory, Human Genetic Department, Research Institute of Rare Diseases, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
Garcia Del Muro X:
Oncology Department, ICO-IDIBELL, Barcelona, Spain
Esteller M:
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain
Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Catalonia, Spain
Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain
Sturm D:
Hopp Childrens Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Heidelberg, Germany
Ecker J:
Hopp Childrens Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany
Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Heidelberg, Germany
Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
Milde T:
Hopp Childrens Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany
Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Heidelberg, Germany
Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
Pfister SM:
Hopp Childrens Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Heidelberg, Germany
Korshunov A:
Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany
Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
Snuderl M:
Department of Pathology, New York University School of Medicine, New York, USA
Mechtersheimer G:
Department of General Pathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
Schüller U:
Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Children's Cancer Center Hamburg, Research Institute, Hamburg, Germany
Jones DTW:
Hopp Childrens Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany
Pediatric Glioma Research Group, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany
von Deimling A:
Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany.
Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.
Green Submitted, Green Accepted
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