The advent of precision epigenetics for medulloblastoma.

Abstract

Medulloblastoma (MB) is the most common and fatal malignant pediatric brain tumor, is located in the cerebellum and is associated with significant therapyrelated morbidity [1]. MB can be subdivided into four clinically and molecularly distinct groups: wingless (WNT), sonic hedgehog (SHH), and groups 3 and 4 [2]. The standard of care for MB patients irrespective of group consists of surgical resection, cranio-spinal radiation and combination chemotherapy. This intensive regimen improves survival, especially in WNT-MB patients. SHH and group 4 patients have intermediate benefit, while most group 3 patients relapse and die from the disease. Moreover, therapy-induced damage to the developing brain remains a significant problem: young survivors suffer from life-long cognitive, neurological and neuroendocrine side effects. Less toxic novel therapies are urgently needed to improve quality of life of these children and young adults. Genomic studies have identified frequent alterations in epigenetic regulators in MBs, suggesting that incorporating epigenetic reprogramming therapy into the standard of care for MB patients may be beneficial and potentially less toxic. Polycomb group proteins are transcriptional repressors essential for normal gene regulation during development and are perturbed in a wide range of human cancers. They usually belong to either of two protein complexes: Polycomb Repressive Complex 1 (PRC1) that adds a ubiquityl moiety to histone H2A at lysine 119 (H2AK119ubl) and PRC2 that catalyzes the addition of one to three methyl groups to histone H3 at lysine 27, leading to H3K27me1, H3K27me2 and H3K27me3 [3]. EZH2, the catalytic component of PRC2, writes the suppressive chromatin marker H3K27me3 and is Research Perspective