학술논문
Recurrent atypical teratoid/rhabdoid tumors (AT/RT) reveal discrete features of progression on histology, epigenetics, copy number profiling, and transcriptomics.
Document Type
Academic Journal
Author
Johann PD; Paediatric and Adolescent Medicine, Swabian Children's Cancer Center Augsburg, EU-RHAB Trial Center, Germany and Bavarian Cancer Research Center (BZKF), Augsburg, Germany.; Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Research Consortium (DKTK), Heidelberg, Germany.; Altendorf L; Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Research Institute Children's Cancer Center Hamburg, Martinistraße 52, N63, 20251, Hamburg, Germany.; Efremova EM; Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Research Institute Children's Cancer Center Hamburg, Martinistraße 52, N63, 20251, Hamburg, Germany.; Holsten T; Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Research Institute Children's Cancer Center Hamburg, Martinistraße 52, N63, 20251, Hamburg, Germany.; Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Steinbügl M; Paediatric and Adolescent Medicine, Swabian Children's Cancer Center Augsburg, EU-RHAB Trial Center, Germany and Bavarian Cancer Research Center (BZKF), Augsburg, Germany.; Nemes K; Paediatric and Adolescent Medicine, Swabian Children's Cancer Center Augsburg, EU-RHAB Trial Center, Germany and Bavarian Cancer Research Center (BZKF), Augsburg, Germany.; Eckhardt A; Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Research Institute Children's Cancer Center Hamburg, Martinistraße 52, N63, 20251, Hamburg, Germany.; Department of Radiotherapy and Radio-Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Kresbach C; Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Research Institute Children's Cancer Center Hamburg, Martinistraße 52, N63, 20251, Hamburg, Germany.; Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Bockmayr M; Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Research Institute Children's Cancer Center Hamburg, Martinistraße 52, N63, 20251, Hamburg, Germany.; Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Koch A; Institute of Neuropathology, Charité, Universitätsmedizin Berlin, Berlin, Germany.; Haberler C; Institute of Neurology, Medical University of Vienna, Vienna, Austria.; Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.; Antonelli M; Department of Radiological, Oncological and Anatomic Pathology Sciences, Università Sapienza, Rome, Italy.; DeSisto J; Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, CO, USA.; Schuhmann MU; Division of Pediatric Neurosurgery, Department of Neurosurgery, Eberhard Karl's University Hospital of Tübingen, Tübingen, Germany.; Hauser P; Second Department of Pediatrics, Semmelweis University, Budapest, Hungary.; Siebert R; Institute of Human Genetics, Ulm University & Ulm University Medical Center, Ulm, Germany.; Bens S; Institute of Human Genetics, Ulm University & Ulm University Medical Center, Ulm, Germany.; Kool M; Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Research Consortium (DKTK), Heidelberg, Germany.; Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.; Green AL; Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, CO, USA.; Department of Pediatrics, University of Colorado Denver, Aurora, CO, USA.; Hasselblatt M; Institute of Neuropathology, University Hospital Münster, Münster, Germany.; Frühwald MC; Paediatric and Adolescent Medicine, Swabian Children's Cancer Center Augsburg, EU-RHAB Trial Center, Germany and Bavarian Cancer Research Center (BZKF), Augsburg, Germany.; Schüller U; Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. u.schueller@uke.de.; Research Institute Children's Cancer Center Hamburg, Martinistraße 52, N63, 20251, Hamburg, Germany. u.schueller@uke.de.; Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. u.schueller@uke.de.
Source
Publisher: Springer Verlag Country of Publication: Germany NLM ID: 0412041 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1432-0533 (Electronic) Linking ISSN: 00016322 NLM ISO Abbreviation: Acta Neuropathol Subsets: MEDLINE
Subject
Language
English
Abstract
Atypical teratoid/rhabdoid tumors (AT/RT) are the most common malignant brain tumors manifesting in infancy. They split into four molecular types. The major three (AT/RT-SHH, AT/RT-TYR, and AT/RT-MYC) all carry mutations in SMARCB1, the fourth quantitatively smaller type is characterized by SMARCA4 mutations (AT/RT-SMARCA4). Molecular characteristics of disease recurrence or metastatic spread, which go along with a particularly dismal outcome, are currently unclear. Here, we investigated tumor tissue from 26 patients affected by AT/RT to identify signatures of recurrences in comparison with matched primary tumor samples. Microscopically, AT/RT recurrences demonstrated a loss of architecture and significantly enhanced mitotic activity as compared to their related primary tumors. Based on DNA methylation profiling, primary tumor and related recurrence were grossly similar, but three out of 26 tumors belonged to a different molecular type or subtype after second surgery compared to related primary lesions. Copy number variations (CNVs) differed in six cases, showing novel gains on chromosome 1q or losses of chromosome 10 in recurrences as the most frequent alterations. To consolidate these observations, our cohort was combined with a data set of unmatched primary and recurrent AT/RT, which demonstrated chromosome 1q gain and 10 loss in 18% (n = 7) and 11% (n = 4) of the recurrences (n = 38) as compared to 7% (n = 3) and 0% (n = 0) in the primary tumors (n = 44), respectively. Similar to the observations made by DNA methylation profiling, RNA sequencing of our cohort revealed AT/RT primary tumors and matched recurrences clustering closely together. However, a number of genes showed significantly altered expression in AT/RT-SHH recurrences. Many of them are known tumor driving growth factors, involved in embryonal development and tumorigenesis, or are cell-cycle-associated. Overall, our work identifies subtle molecular changes that occur in the course of the disease and that may help define novel therapeutic targets for AT/RT recurrences.
(© 2023. The Author(s).)
(© 2023. The Author(s).)