Brain tumors are the most common solid malignancy in children and pediatric low grade gliomas (PLGG) are the most common childhood brain cancer accounting for 42% of pediatric brain tumors. PLGG possess the dichotomy of excellent (>90%) short term overall survival with very low (<40%) progression free survival leading to the following major clinical challenges:
1) Multiple recurrences resulting in accumulation of toxic therapies.
2) Significant but extremely variable long term morbidity resulting in late mortality.
3) Multiple pathological subgroups lumped together resulting in lack of specific and targeted therapies.
In this project, in order to address these issues, Dr. Uri Tabori and colleagues, Sick Kids of Toronto, hypothesize that uncovering RAS/MAPK alterations in all PLGG subtypes as well as secondary events in these cancers will enable novel molecular risk stratification of PLGG. This novel classification will guide current and future targeted therapies which are becoming available for these tumors. The study encompasses the following four objectives:
- To define all RAS/MAP Kinase pathway alterations in a large cohort of clinically relevant PLGG patients, including:
- BRAF-KIAA1549 fusions
- Other BRAF and RAS gene fusions
- BRAF mutation
- Non-BRAF gene alterations in the RAS/MAPK pathway.
- To determine the role of secondary events in the biological behavior of PLGG, including:
- CDKN2A deletions
- Copy number aberrations
- Epigenetic modifiers including histone mutations and HTERT promoter mutations.
- To investigate progressive genetic alterations in patients with multiple recurrences, including:
- Rates of various alterations and correlations with number of progressions
- Change or additional alterations in tumors with multiple progressions.
- To correlate findings of aims 1-3 with clinical outcomes for progression free survival and long term overall survival.