Long-term outcome and surrogate molecular signatures of pediatric patients with diffuse astrocytomas
Diffuse astrocytomas is the major cause of mortality in pediatric neurooncology. Pediatric diffuse astrocytomas are clinically and biologically heterogeneous, they consist of distinct subtypes driven by various molecular events. Our aim was to reveal if the surrogate molecular signatures reflecting molecular alterations underlying diffuse astrocytomas could be of prognostic value. The surrogate molecular signature was determined by IHC with antibodies to IDH1R132H, p53, BRAF V600E, H3K27trimethylated, ATRX and by cytogenetics with identification of deletion CDKN2A and FGFR2 fusion. As a result, we obtained 6 groups of diffuse astrocytomas with different surrogate molecular signatures, which we designated as H3K27mut, ALT, IDH1mut, BRAFmut-PXA, BRAF mut/FGFR2, MYB. A total of 62 patients (29 male, 33 female, mean age 10,6 years, range 0-18 years) were analyzed. The study was approved by the Independent Ethics Committee and the Scientific Council of the Belarusian Research Center for Pediatric Oncology, Hematology and Immunology (Republic of Belarus). These surrogate molecular signatures were associated with significantly different outcomes, i.e. BRAFmut/FGFR2, MYB groups show a significantly good prognosis with 100% overall survival and relapse-free survival of 89 ± 11% and 100%. Groups H3K27mut, ALT, IDH1mut, BRAFmut-PXA display extremely poor outcomes with EFS equal to 0%, 20 ± 17%, 44 ± 17%, 18 ± 12% respectively, and OS equal to 23 ± 19%, 37 ± 20%, 40 ± 17%, 53 ± 19% respectively. The recognition of subtypes of pediatric diffuse astrocytomas based on surrogate molecular signature revealed close correlations with biological parameters and clinical outcomes and may therefore, be predictive of response to standard treatment protocols.