BIOM-61. EXPLORING HOMOLOGOUS RECOMBINATION DEFICIENCY IN PEDIATRIC HIGH-GRADE GLIOMAS

Abstract

Abstract Homologous recombination deficiency (HRD) has been extensively studied in breast cancer and ovarian cancer given its correlation with sensitivity to Poly (ADP-ribose) polymerases (PARP) inhibitors. In these cancers, HRD is most frequently caused by biallelic inactivation of BRCA1/2 and tumors often exhibit ‘genomic scars’ such as elevated HRD.sum score and specific mutational signatures, including specific single nucleotide variant (SNV), small insertion/deletion (Indel), and structural variant (SV) signatures. Despite its clinical relevance, HRD has not been systematically studied in pediatric cancers and its therapeutic predictive value is unknown. Here, we evaluated HRD in 255 tumor-normal paired whole-genome-sequenced (WGS) samples of pediatric high-grade glioma (pHGG) and 23 tumor-normal paired WGS samples of breast cancer (BC) as comparison. We found that 9% of the pHGG samples have HRD.sum score greater than 40, an indicator of HRD in several adult cancers. However, while we identified HRD-related SNV signature SBS3 and SV signature RS5 in some of the pHGG samples, HRD-related Indel signature ID6 was not identified. We also evaluated two composite scores, namely, HRDetect and CHORD, on our samples. While virtually all BC samples with BRCA1/2 loss were predicted to be HRD by both scores, none of the pHGG samples was predicted to be HRD by either score. We profiled somatic and germline variants from over 500 DNA damage response genes in the pHGG samples and identified TP53 as the most frequently mutated genes with biallelic loss, whereas biallelic loss of BRCA1/2 was not found. Overall, our study suggests that HRD exists in a fraction of pHGG samples, but is driven by inactivation of genes other than BRCA1/2, resulting in a different set of genomic scars compared to those in BCs. Functional analysis of sensitivity to PARP inhibitor and related DNA damage inhibitors is ongoing to evaluate potential therapeutic relevance of these genomic scars.