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MAGIC - Medulloblastoma Advanced Genomics International Consortium

Stratifying and Targeting Pediatric Medulloblastoma through Genomics

Project Leaders Michael Taylor , Marco Marra , David Malkin
Project Co-Investigators Cynthia Hawkins, Carlo Marra, Donald Mabbott, Eric Bouffet, Gary Bader, Jennifer Chan, James Rutka, Nada Jabado, Steven Jones , Stefan Pfister, Scott Pomeroy, Stephen Scherer, Yoon-Jae Cho
Project Contacts

For all project related inquires contact:

Dominik Stoll
Involved Organizations
Funding Agencies
Hospital for Sick Children (SickKids) - Chief of Research Fund

The Brain

Overview

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Cancer is the leading cause of non-accidental death in children, and brain tumors (medulloblastoma) are the leading cause of pediatric cancer deaths in Canada. Those children who do manage to survive usually have a severely impaired quality of life due to the aggressive treatment for the disease. Strategies are needed to improve the quality of life for families of children with brain tumors, to increase survival rates, and to minimize the impact on health care systems.

Preliminary data suggests that some children with very good prognosis medulloblastoma are being over-treated with current regimens and could be spared complications by reducing the amount or type of treatment they receive. On the other hand, some children with very poor prognosis medulloblastoma die despite going through painful therapies that may in fact be futile. Reducing therapy in this group of patients could increase quality of life without changing their prognosis.

In this project, genomic analyses of pediatric medulloblastoma samples, obtained through the international medulloblastoma consortium, will be performed. mRNA and miRNA expression profiles of 1000 samples, representing all four subgroups (Wnt, Shh, Group C, and D), will be studied to identify novel subtypes within each subgroup. The resulting subtype-specific expression profiles will support the development of reliable and robust biomarkers to more accurately and reliably classify medulloblastomas for treatment in clinical trials. For that purpose, two assays will be developed: an antibody-based immunohistochemical assay and an orthogonal nucleic acid-based hybridization assay.

Additional genomic DNA analysis of the 300 high risk subgroup cases will support the discovery of subgroup specific somatic mutations in order to inform current clinical trials of targeted therapies, and to identify genes and pathways already targeted in other diseases. Such therapies could be rapidly transitioned to Phase II trials in medulloblastoma. Furthermore, the discovery of somatic mutations could be used for developing as well as validating specific biomarkers.

The project team will also try to identify risk factors that predispose children to this type of cancer. Subgroups of children with medulloblastoma who have poor quality of life will be prioritized, and the team will work with families to quantify the additional risks they are willing to assume in reducing therapy to improve quality of life. The results of these experiments can very quickly inform global childhood clinical trials consortia to initiate trials of therapy- sparing treatment of medulloblastoma. It is anticipated that these studies will transform the way that children with medulloblastoma are treated and will have an immediate and lasting positive impact on both the survival and quality of life of children with this disease.

Recent MAGIC publications:

Subgroup-specific structural variation across 1,000 medulloblastoma genomes. Northcott PA, Shih DJ, et al., Nature. 2012 Aug 2;488(7409):49-56.

Rapid, reliable, and reproducible molecular sub-grouping of clinical medulloblastoma samples. Northcott PA, Shih DJ, Remke M, Cho YJ, Kool M, Hawkins C, Eberhart CG, Dubuc A, Guettouche T, Cardentey Y, Bouffet E, Pomeroy SL, Marra M, Malkin D, Rutka JT, Korshunov A, Pfister S, Taylor MD. Acta Neuropathol. 2011 Nov 6. [Epub ahead of print]


For all project related inquiries please contact:

Dominik Stoll, Project Manager
Genome Sciences Centre, BC Cancer Agency
Email: dstoll@bcgsc.ca
Phone: 604-707-5900 x 675410