HGG-23. DECIPHERING THE RELATIONSHIP OF MICROSATELLITE-INSTABILITY AND MUTATIONAL BURDEN IN HIGH-GRADE GLIOMA PATIENTS WITH CONSTITUTIONALLY IMPAIRED DNA DAMAGE RESPONSE

Abstract Multiple large-scale genomic studies across pediatric tumors have reported an overall frequency of ~6-10% patients with constitutional pathogenic variants, but associations cancer predisposition distinct tumor types vary between zero and 100%. We analyzed sequencing DNA methylation data from 363 to explore the landscape in high-grade gliomas (pedHGG). Almost all pedHGG alterations resulting mismatch repair deficiency (MMRD) were classified IDH-mutant or pedRTK1a classes. Conversely, 70% nearly 60% (<18 years) arose either Lynch cMMRD syndromes. Biallelic MMR inactivation (cMMRD) was found almost exclusively affect exchangeable part machinery complex (MSH6/PMS2; 75%), while heterozygous loss affected non-exchangeable core members MLH1 MSH2 (93%). MMRD showed substantially lower mutational burden (TMB < 40), less microsatellite instability, frequent MSH6 mutation (60%), pedRTK1-MMRD often harbored additional POLE, leading ultra-mutator phenotype 100), had higher instability burden, more linked PMS2 loss. Both IDH-mutant- associated poor outcome, MMRD-associated significantly shorter survival compared sporadic (p=0.0015). observed a nonlinear correlation increasing numbers point mutations, InDels instability. Exemplary, variants number TMB, which might be due ability replacement protein MSH3. As newer towards important role antigen presentation therefore as potential biomarker for immune checkpoint inhibition, further exploration these detailed molecular conjunction clinical outcome response is warranted.