Molecular Biology of Childhood Brain Tumours

• Main Author: Kumar, Sachin Anand
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01-01-2021
• Subjects: Cellular biology
• ISBN: 9798496544764

Malignancies of the central nervous system are the leading cause of cancer-related death in children. These cancers pose a significant clinical burden due to limited treatment options and substantial morbidity from chemotherapy and radiation sequelae during childhood. Two of the most common pediatric brain tumours are medulloblastoma and ependymoma. Over the past decade, advances in genomics have allowed for these tumours to be classified into molecularly and clinically distinct subgroups. These studies have enabled researchers to identify drivers of tumorigenesis, uncover novel vulnerabilities, and propose putative targeted treatments. In this thesis, I continue to build upon these findings. First, examining the genetic landscape of non-coding mutations in medulloblastoma we identify a highly recurrent mutation in the U1 small nuclear RNA. These mutations are prognostically relevant, represent a novel type of splicing-related mutation, and provide a new avenue to develop targeted immunotherapies. Next, we establish primary patient derived models of the lethal PFA ependymoma subgroup. Through a series of experiments, we characterize a metabolic-epigenetic axis that drives PFA growth and propose a “Goldilocks Model” of PFA tumorigenesis. Finally, we establish that the metabolic phenotype of PFA mirrors that of normal cerebellar development. Thus, characterizing the molecular biology of medulloblastoma and ependymoma has revealed novel drivers of disease, advancing our capacity to develop targeted treatments for these dismal cancers.