Welcome to the International Childhood Astrocytoma Novel Genomics and Epigenomics strategies Consortium project
Primary brain tumors are the leading cause of cancer-related death in children under the age of 20, surpassing leukemias, and are the third leading cause of cancer-related death in young adults aged 20-39 years. High grade astrocytomas (HGA) include glioblastoma (GBM) and are the most common brain cancer in adults. Every year 200 children and 300 young adults in Canada will be affected and 90% will die within 3 years of diagnosis. Thus HGA remain mostly incurable and is an economic and societal challenge, and a significant burden of suffering.
Our team established the ICHANGE consortium that groups samples and expertise across the world, and helped revolutionize our understanding of HGA in children. Our findings showed that HGA in children involve major changes in the chromatin architecture. We identified recurrent somatic driver mutations affecting lysine (K) 27 and 36, two critical residues in the histone 3 variant 3 (H3.3). We further showed that H3.3 mutations tightly correlate with a distinct global DNA methylation pattern, and that each has a specific patient age range and neuroanatomical localization. These findings position us and Canada as major international leaders in the field of HGA. Importantly, they confirm HGA is heterogeneous and explain why current highly toxic and costly “blanket” treatments are not effective.
Our aims are to:
1) Develop and validate diagnostic tests of H3 mutations in H3 variants in cancer.
2) Uncover critical alterations caused by H3 mutations and the alterations in HGA wild-type for these mutations using integrated in-depth analysis of the methylome, genome, and transcriptome of 100 HGA(Y1-4) 3) Use experimental “companion” models of H3 mutations to reposition or screen novel and known compounds affecting histone marks (the epigenome, collaboration with pharmaceutical companies.