Key points are not available for this paper at this time.
Abstract BACKGROUND Medulloblastoma (MB) is one of the most frequent high-grade brain tumor types of childhood and adolescence. Based on biology, histology, and its clinical course, MB is a heterogeneous disease with four different molecular types (WNT, SHH, Group 3, and Group 4), which are most reliably distinguishable by their global DNA methylation pattern. METHODS We analyzed DNA methylation (n=47), copy number variants, transcriptomic data (n=7) and histology (n=28) of a previously unrecognized type of MB. RESULTS As a result of integrating DNA methylation data of 2, 600 MB and screening of 140, 000 data sets uploaded to the DKFZ brain tumor classifier (www. molecularneuropathology. org), we identified a small group of MB that displayed a homogeneous DNA methylation pattern, which was clearly distinct from previously known MB types. Tumors within this group have also been recognized as a separate methylation class by latest versions of the classifier, which has provisionally been named medullomyoblastoma (MBMYO). Transcriptomic data were similarly distinct from other MB types. Comparison of these data to various cell types of the developing hindbrain revealed transcriptional similarities to precursor cells of the rhombic lip with signatures of WNT signaling and myogenic differentiation. In line with the latter findings, 2/11 cases with DNA sequencing data harbored hotspot CTNNB1 mutations and 5/28 cases showed a myogenic differentiation based on histology. MYC amplifications were present in 11/47 cases, corresponding to a higher fraction of MYC-amplified tumors compared to all known MB types. Median age at diagnosis in this cohort was 16 years, and five-year overall survival was ~75 %. CONCLUSIONS In summary, we describe a novel type of MB identified by DNA methylation profiling that likely needs to be addressed separately during the retrospective analyses of MB patient cohorts, for the design of future clinical trials, and when evaluating targeted therapies.
Eckhardt et al. (Tue,) studied this question.