Browsing by Author "von Deimling, A"

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Primary central nervous system sarcoma with DICER1 mutation-treatment results of a novel molecular entity in pediatric Peruvian patients
(John Wiley and Sons Inc., 2021) Diaz Coronado, RY; Mynarek, M; Koelsche, C; Mora Alferez, P; Casavilca, 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; Garcia Leon, JL
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.
Primary intracranial spindle cell sarcoma with rhabdomyosarcoma-like features share a highly distinct methylation profile and DICER1 mutations
(Springer Verlag, 2022) 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; Casavilca Zambrano, Sandro; 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; von Deimling, A
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.