HGG-45. COMPREHENSIVE MOLECULAR CHARACTERIZATION OF PEDIATRIC TREATMENT-INDUCED HIGH-GRADE GLIOMA: GERMLINE DNA REPAIR DEFECTS AS A POTENTIAL ETIOLOGY

Abstract

BACKGROUND

Pediatric treatment-induced high-grade glioma (TIHGG) is an incurable late complication of cranial radiation therapy or combined radiation/chemotherapy. Previously, we showed TIHGG gene expression differs from spontaneous pediatric HGG and defined two TIHGG groups (A & B) by transcriptomic profiling. We now report copy-number analysis, whole genome sequencing (WGS), and methylation profiling for an expanded TIHGG cohort.

METHODS

Illumina Infinium 450/850K methylation analysis was performed on 34 TIHGG samples from a multi-institutional/Childhood Cancer Survivors Study Group cohort. WGS was performed on tumor and matched germline DNA from 15 TIHGGs.

RESULTS

On methylation profiling, 19/27 TIGs, including all expression group A and B cases (6 each), clustered into a subclass of IDH-wt midline GBM. Recurrent copy number alterations included 1p loss (13/34), 1q gain (13/34), ch13 loss (13/34), PDGFRA gain/amplification (17/34), and CDKN2A loss (14/34). WGS identified a mean germline mutation load of 1.50 mut/Mb. Mean somatic mutation load, excluding one hypermutator sample, was 0.12 and 1.08 mut/Mb for TIHGG expression groups A and B, respectively (p<0.002). All TIHGG group B cases had pathogenic germline alterations in BARD1 or BRCA1, which repair DNA damage from ionizing radiation. TIHGG expression group A samples lacked pathogenic DNA repair mutations, except the hypermutator sample, which had distinct germline DNA repair defects including BRCA2 and ATR.

CONCLUSIONS

TIHGGs are enriched for distinctive chromosomal aberrations and cluster into a defined epigenetic subgroup. A subset of TIHGGs have a high somatic mutational load, likely from germline defects in homologous recombination, which could predict TIHGG risk before treatment.