Integrative functional genomics of recurrent childhood medulloblastoma

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Irrespective of entity, patients who relapse from cancer have an extremely dismal outlook, with nearly all patients succumbing to their recurrent disease. This is particularly true for patients with medulloblastoma (MB), the most common malignant brain tumor in children, where tumor relapse is among the most powerful predictors of prognosis despite therapeutic intervention and clinical trial enrollment.

In contrast to what has been learned through studying treatment naïve diagnostic samples, little is known about the molecular genetics of MB relapse, a profound predictor of poor outcome in affected children. Although MB subgroup status remains stable at relapse, the degree to which somatic driver events are conserved or divergent between these disease states is currently unknown. Recent candidate gene approaches have demonstrated anecdotal differences between patient-matched primary/relapse pairs that may have important clinical implications. However, systematic, genome-wide studies designed to effectively investigate the molecular relationship between diagnostic and relapsed MB in a sizable cohort have yet to be reported. Moreover, whether or not MB relapses spawn from rare, treatment-resistant subclones present in the primary tumor, as has recently been proposed in other entities has yet to be substantiated. Since the next generation of MB clinical trials will begin to evaluate targeted therapies in patients with relapsed disease, understanding how MB relapses are related to the primary tumors from which they arise will be paramount, as will identification and validation of the molecular targets emerging at relapse secondary to cytotoxic chemotherapy and radiation.

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What are the goals of this project?

The goals of this project are to assess the conservation and divergence of already generated (CBTN) genomic and transcriptional landscapes in patient-matched primary/relapse MB pairs, assess methylation profiles in patient-matched primary/relapse MB pairs and functionally validate and therapeutically target molecular events enriched at MB relapse.

What is the impact of this project?

In order to define attractive therapeutic targets for more effective treatment of recurrent disease, systematic, integrative genomic studies of MB relapse are desperately needed. Comprehensive evaluation of the genomic similarities and differences contributing to primary versus relapse MB coupled with inference of the clonal composition of these disease compartments will dramatically advance our understanding of the molecular and cellular basis of recurrent MB. Subsequent functional validation of thematic pathways determined to be enriched at relapse will provide essential systems for evaluating novel therapies for the treatment of MB relapse and inform design of future MB relapse clinical trials. These studies will be vital to overcome the currently unacceptably dismal outlook for patients and families affected by MB relapse.

Specimen Data

The Children's Brain Tumor Network contributed to this project by providing tumor DNA.