A proteomics study of medulloblastoma samples — published in Cancer Cell — harnessed genomic and transcriptional analyses to identify new subtypes that had not previously been found. The findings may lead to more precise biomarkers for the characterization of medulloblastoma tumors and potential new therapeutic targets.
The study included samples from 45 patients representing each of the 4 subgroups of medulloblastoma: wingless (WNT), Sonic hedgehog (SHH), group 3, and group 4.1 A multi-institutional team led by researchers at Boston Children’s Hospital, Massachusetts Institute of Technology (MIT), and the Broad Institute profiled the protein and phospho-protein composition of the samples in conjunction with mutational, transcriptional, and DNA copy number analyses.
“Work that has been done before, measuring messenger RNA [mRNA] and drawing correlations with changes in DNA copy number, has taken us a certain distance to define subgroups, but we really only have clear mechanisms for WNT and Sonic hedgehog, which are driven by activation of those 2 pathways. [Group 3 and group 4] comprise 60% of these tumors, and their mechanisms are ambiguous,” said Scott Pomeroy, MD, PhD, neurologist at Boston Children’s Hospital and one of the lead investigators of the current study.
The researchers found 2 subtypes of group 3 based on proteomic analysis. The first, group3a, was characterized by activation of the Myc transcription factor and associated with poorer prognosis. Group 3a was similar to a subtype of group 3 that had previously been defined based on DNA copy number and transcriptional analyses. However amplification of the Myc gene is not present in all tumors of this subtype, and was found in only 2 of the 8 group 3a samples in the current study. In contrast, the investigators detected increased phosphorylation and acetylation of Myc protein in all 8 group 3a samples.
Furthermore, proteomic and phospho-proteomic analyses pointed to proteins that may regulate Myc activity. They revealed that PRKDC, a kinase that has been shown in vitro to stabilize Myc, and its targets were elevated in group 3 and Wnt samples. The researchers demonstrated that a PRKDC inhibitor rendered a Myc-active cell line more sensitive to radiation. They also found that levels of deubiquitinating enzymes, which may stabilize Myc, were higher in group 3a than 3b samples. “If we could unblock the degradation of Myc, that may be another way to more effectively treat the cancer,” Dr Pomeroy said.