Genetic landscape of large cell/anaplastic medulloblastoma – more than one disease

Medulloblastom is the most common malignant pediatric brain cancer. The large cell/anaplastic type of MB is characterized by poor survival. We collected FFPE samples of 155 LC/A MB with a median age of 9 years, and performed a systematic histological, immunohistochemical and genetic analysis by next-generation panel sequencing (NGS), 450k/850k methylation bead-array hybridization and molecular inversion probe array. Methylation-based subtyping and NGS panel sequencing showed that the cohort of LC/A MB represent different biological entities: 8% WNT-MB, 18% SHH-MB to be divided in 58% SHH TP53-activated and 42% SHH TP53-wildtype and 69% non-WNT/non-SHH-MB (68% Grp3 and 32% Grp4). Copy profiling by MIP showed MYC amplification, mostly in Grp3 MB; 82% of them in methylation subtype II of Grp3 MB. Focal gains of OTX2 were present in 54 % of cases (all subgroups) and i17q in 86% of non-WNT/non-SHH. By NGS we detected recurrent mutations in 37 MB-related genes; most frequent were TP53 (16%; mostly in SHH-TP53mut and WNT), KMT2D (9%; all types), CTNNB1 (9%; only WNT), and PIK3CA (9%, mostly in SHH-TP53wt and WNT). Our data demonstrate that LC/A MB represent different biological entities.

Publication History

Article published online:
17 May 2022