Primary central nervous system sarcoma with DICER1 mutation-treatment results of a novel molecular entity in pediatric Peruvian patients
Por:
Diaz Coronado RY, Mynarek M, Koelsche C, Mora Alferez P, Casavilca Zambrano S, Wachtel Aptowitzer A, Sahm F, von Deimling A, Schüller U, Spohn M, Sturm D, Pfister SM, Morales-La Madrid A, Sernaque Quintana R, Sarria Bardales G, Negreiros Chinchihuara T, Ojeda Medina L, Garcia-Corrochano Medina P, Campos Sanchez DA, Ponce Farfan J, Rutkowski S and Garcia Leon JL
Publicada:
15 feb 2022
Ahead of Print:
1 oct 2021
Resumen:
Background A high frequency of primary central nervous system (CNS) sarcomas was observed in Peru. This article describes the clinical characteristics, biological characteristics, and outcome of 70 pediatric patients. Methods Data from 70 pediatric patients with primary CNS sarcomas diagnosed between January 2005 and June 2018 were analyzed. DNA methylation profiling from 28 tumors and gene panel sequencing from 27 tumors were available. Results The median age of the patients was 6 years (range, 2-17.5 years), and 66 of 70 patients had supratentorial tumors. DNA methylation profiling classified 28 of 28 tumors as primary CNS sarcoma, DICER1 mutant. DICER1 mutations were found in 26 of 27 cases, TP53 mutations were found in 22 of 27 cases, and RAS-pathway gene mutations (NF1, KRAS, and NRAS) were found in 19 of 27 tumors, all of which were somatic (germline control available in 19 cases). The estimated incidence in Peru was 0.19 cases per 100,000 children (<18 years old) per year, which is significantly higher than the estimated incidence in Germany (0.007 cases per 100,000 children [P < .001). Patients with nonmetastatic disease (n = 46) that were treated with a combination therapy had a 2-year progression-free survival (PFS) rate of 58% (95% CI, 44%-76%) and a 2-year overall survival rate of 71% (95% CI, 57%-87%). PFS was the highest in patients treated with chemotherapy with ifosfamide, carboplatin, and etoposide (ICE) after upfront surgery followed by radiotherapy and ICE (2-year PFS, 79% [59%-100%], n = 18). Conclusions Primary CNS sarcoma with DICER1 mutation has an aggressive clinical course. A combination of surgery, chemotherapy, and radiotherapy seems beneficial. An underlying cancer predisposition syndrome explaining the increased incidence in Peruvian patients has not been identified so far. Lay Summary A high incidence of primary pediatric central nervous system sarcomas in the Peruvian population is described. Using sequencing technologies and DNA methylation profiling, it is confirmed that these tumors molecularly belong to the recently proposed entity "primary central nervous system sarcomas, DICER1 mutant." Unexpectedly, DICER1 mutations as well as all other defining tumor mutations (TP53 mutations and RAS-pathway mutations) were not inherited in all 19 patients where analyzation was possible. These tumors have an aggressive clinical course. Multimodal combination therapy based on surgery, ifosfamide, carboplatin, and etoposide chemotherapy, and local radiotherapy leads to superior outcomes.
Filiaciones:
Diaz Coronado RY:
Pediatric Oncology Department, Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru
Delgado Clinic, Auna, Lima, Peru
Mynarek M:
Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Koelsche C:
Department of Pathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
Mora Alferez P:
Genetics Department, Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru
Casavilca Zambrano S:
Pathology Department, Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru
Wachtel Aptowitzer A:
Pediatric Oncology Service, Anglo Americana Clinic, Lima, Peru
Sahm F:
Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
Clinical Cooperation Unit Neuropathology, German Cancer Research Center, Heidelberg, Germany
von Deimling A:
Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
Clinical Cooperation Unit Neuropathology, German Cancer Research Center, Heidelberg, Germany
Schüller U:
Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Research Institute Children's Cancer Center, Hamburg, Germany
Institute of Neuropathology, University Medical Center Hamburg Eppendorf, Hamburg, Germany
Spohn M:
Research Institute Children's Cancer Center, Hamburg, Germany
Bioinformatics Core Facility and Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Sturm D:
University Medical Center, Heidelberg, Germany
Hopp Children's Cancer Center Heidelberg, Heidelberg, Germany
Pediatric Glioma Research Group, German Cancer Research Center, Heidelberg, Germany
Pfister SM:
University Medical Center, Heidelberg, Germany
Hopp Children's Cancer Center Heidelberg, Heidelberg, Germany
Division of Pediatric Neurooncology, German Cancer Consortium and German Cancer Research Center, Heidelberg, Germany
Morales-La Madrid A:
Pediatric Oncology Department, Neuro Oncology Unit, Hospital San Joan De Deu, Barcelona, Spain
Sernaque Quintana R:
Radiology Department, Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru
Sarria Bardales G:
Delgado Clinic, Auna, Lima, Peru
Radiotherapy Department, Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru
Negreiros Chinchihuara T:
Radiotherapy Department, Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru
Ojeda Medina L:
Neurosurgery Department, Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru
Garcia-Corrochano Medina P:
Neurosurgery Department, Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru
Campos Sanchez DA:
Neurosurgery Service, Anglo Americana Clinic, Lima, Peru
Ponce Farfan J:
Pediatric Oncology Service, Anglo Americana Clinic, Lima, Peru
Rutkowski S:
Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Garcia Leon JL:
Pediatric Oncology Department, Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru
Delgado Clinic, Auna, Lima, Peru
Pediatric Oncology Service, Anglo Americana Clinic, Lima, Peru
Bronze
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