By integrating genomic and transcriptional analyses with proteomic data, the researchers uncovered “surprising” proteomic heterogeneity among SHH tumors that was not reflected in the mRNA levels, Dr Pomeroy said. They described 2 proteomic-based subtypes of SHH: SHHa, which had higher levels of proteins associated with mRNA processing, DNA repair, and the Myc pathway; and SHHb, marked by elevated levels of proteins associated with neuronal activity, such as those seen in the glutamatergic synaptic pathway.
“This study could impact clinical trial design by impacting our selection of what new drugs we would like to test, as nowadays, the design of even early-phase trials is based more on science like this that gives us logical targets,” said Sarah Leary, MD, a pediatric neuro-oncologist at Seattle Children’s in Washington.
The findings could also lead to better biological markers for risk stratification and treatment decisions, said Dr Leary, who was not involved in this study. For example, she explained, scientists can now probe samples from large medulloblastoma trials through Children’s Oncology Group to ask whether elevated levels of proteins identified in this study are predictive of poorer treatment response among participants in former trials.
“In the immediate future, we could adopt measurement of Myc protein in tumor samples as a way to identify more precisely the group 3a subtype,” Dr Pomeroy said. This could be done by immunohistochemistry, which along with gene sequencing is commonly performed by clinicians to characterize the molecular subtype of medulloblastoma samples.
- Archer TC, Ehrenberger T, Mundt F, et al. Proteomics, post-translational modifications, and integrative analyses reveal molecular heterogeneity within medulloblastoma subgroups. Cancer Cell. 2018;34(3):396-410.