Dynamic plasmatic detection of the H3.3 mutation status in patients with high-grade astrocytomas (HGA)

Abstract

The achievements in increasing cure rates and disease control for several subtypes of pediatric cancer in the last decades are undeniable. Yet, high-grade astrocytomas (HGA) are a particularly lethal and disabling form of brain cancer, with barely 10% of children and young adults surviving 3 years after their diagnosis. Worldwide efforts in facing this devastating tumor are evolving. Recently, it was described that somatic H3.3 mutations tightly correlate with a distinct global DNA methylation pattern of pediatric HGA, and that each mutation has a specific patient age range and neuroanatomical localization. Analyzing these unique genetic signatures, allied with better tumor-risk classification and targeted drug-designed compounds are expected to improve outcome in this setting of pediatric cancer. This research proposal is part of a broader ICHANGE consortium that collects samples and expertise across the world. The segment in my trust is to evaluate and validate diagnostic tests of H3.3 mutations in HGA in body fluids by detection of DNA fragments (cell free DNA, cfDNA) containing the specific H3.3 mutations in the brain in body fluids(plasma/urine) from children and young adults with HGA in centers across Canada. Exome sequencing and IHC will be performed on brain tissue to determine H3.3 mutation status in HGA. To validate this assay, follow-up sampling of body fluids at diagnosis, before and after surgery, during therapy and at follow-up will be assessed.These data will be combined to a broader cooperative multicentric trial, which expects to uncover critical alterations caused by H3.3 mutations using integrated in-depth analysis of the methylome, genome, and transcriptome of HGA. In addition, experimental models of H3.3 mutations to reposition or screen novel and known compounds affecting histone marks will be developed. The expected impact of this research is to create a dynamic, reliable and less invasive method for tumor monitoring, and to facilitate treatment decision. This approach is expected to be clinically applicable and it also has the potential to be extended for several other human cancers. (AU)