Primary intracranial spindle cell sarcoma with rhabdomyosarcoma-like features share a highly distinct methylation profile and DICER1 mutations

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 ofDICER1 hotspot mutations (21/22; 95%) and a high frequency of co-occurringTP53 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 ofKRAS (8/22; 36%) and mutations or deletions ofNF1 (7/22; 32%), followed by mutations ofFGFR4 (2/22; 9%),NRAS (2/22; 9%), and amplification ofEGFR (1/22; 5%). A germlineDICER1 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 andDICER1 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 s...
Source: Acta Neuropathologica - Category: Neurology Source Type: research