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Primary central nervous system sarcoma with DICER1 mutation-treatment results of a novel molecular entity in
Rosdali Y Diaz Coronado1,2, Martin Mynarek3, Christian Koelsche4
1Pediatric Oncology Department, Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru.
Insights
Pediatric primary central nervous system (CNS) sarcomas in Peru are frequently DICER1-mutated and aggressive. Combination therapy including surgery, chemotherapy, and radiotherapy improves outcomes, though the cause of the high incidence remains unknown.
Area of Science:
- Pediatric Oncology
- Neuro-oncology
- Molecular Pathology
Background:
- High incidence of primary pediatric central nervous system (CNS) sarcomas observed in Peru.
- Study confirms these tumors are molecularly classified as primary CNS sarcomas, DICER1-mutant.
- Investigates clinical, biological characteristics, and outcomes of 70 pediatric patients.
Purpose of the Study:
- To describe the clinical and biological characteristics of pediatric primary CNS sarcomas in Peru.
- To determine the molecular basis and genetic mutations associated with these tumors.
- To evaluate the treatment outcomes and survival rates in affected children.
Main Methods:
- Analysis of clinical data from 70 pediatric patients diagnosed between 2005 and 2018.
- DNA methylation profiling of 28 tumors and gene panel sequencing of 27 tumors.
- Comparison of incidence rates with Germany and analysis of mutation inheritance patterns.
Main Results:
- All analyzed tumors were classified as primary CNS sarcoma, DICER1-mutant.
- Common mutations include DICER1 (26/27), TP53 (22/27), and RAS-pathway genes (19/27); most were somatic.
- Estimated incidence in Peru (0.19/100,000) is significantly higher than in Germany (0.007/100,000).
- Two-year progression-free survival (PFS) was 58% and overall survival was 71% for nonmetastatic patients on combination therapy.
- Highest 2-year PFS (79%) observed with surgery followed by ICE chemotherapy and radiotherapy.
Conclusions:
- Primary CNS sarcoma with DICER1 mutation follows an aggressive clinical course.
- Multimodal therapy combining surgery, chemotherapy (ICE), and radiotherapy demonstrates beneficial outcomes.
- The underlying cause for the increased incidence in Peruvian children remains unidentified.
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 [<18 years] per year; 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.
