The role of chromatin remodeling in medulloblastoma

Abstract

The unexpectedly high frequency and universality of alterations to the chromatin machinery is one of the most striking themes emerging from the current deluge of cancer genomics data. Medulloblastoma (MB), a malignant pediatric brain tumor, is no exception to this trend, with a wealth of recent studies indicating multiple alterations at all levels of chromatin processing. MB is typically now regarded as being composed of four major molecular entities (WNT, SHH, Group 3 and Group 4), which vary in their clinical and biological characteristics. Similarities and differences across these subgroups are also reflected in the specific chromatin modifiers that are found to be altered in each group, and each new cancer genome sequence or microarray profile is adding to this important knowledge base. These data are fundamentally changing our understanding of tumor developmental pathways, not just for MB but also for cancer as a whole. They also provide a new class of targets for the development of rational, personalized therapeutic approaches. The mechanisms by which these chromatin remodelers are dysregulated in MB, and the consequences both for future basic research and for translation to the clinic, will be examined here.

Figure 1

Chromatin modifier genes recurrently altered in medulloblastoma (MB). This figure indicates those genes related to the GO term “Chromatin Modification” (GO:0015168), which are mutated at least twice in the discovery cohorts (whole‐exome or whole‐genome sequencing, n = 189) of the three next‐generation sequencing studies described herein 30, 57, 62. Percentages by gene names indicate the overall frequency of mutation in this gene across the three studies. NB—cases with no mutation in the listed genes are not shown.

Figure 2

Schematic of key chromatin‐related mutations in medulloblastoma (MB). This schematic view indicates some of the recurrently mutated chromatin modifier genes in medulloblastoma, and their possible effects on disrupting chromatin marks, with a particular focus on the disrupted H3K4/H3K27 methylation frequently observed in Group 3 and Group 4 tumors.