JS04.4.A Beyond β-catenin: Genetic alterations of<i>TP53</i> and<i>OTX2</i> and older age indicate increased risk of relapse in WNT medulloblastomas

Abstract Background This genetic analysis of WNT-activated medulloblastomas (WNT-MBs) aimed to re-evaluate the prognostic impact age, TP53 mutations and identify specific chromosomal aberrations as possible markers. Material Methods In a cohort 191 patients with WNT-MBs, in CTNNB1, APC were analyzed by Sanger and/or NGS panel sequencing. Chromosomal copy number assessed high-resolution, genome-wide molecular inversion probe technology (MIP), SNP6 array, 850k methylation bead-array hybridization. Association prognosis was evaluated 133 follow-up data from HIT2000 medulloblastoma trial, HIT registries, NOA-07 trial. Results CTNNB1 present 92.2% samples. found 6.8% (13 samples). One wildtype tumor gained WNT-activation due homozygous deletion FBXW7. Monosomy 6 78.6%, more frequent children compared adolescents/adults (≥16 years). Adolescents/adults showed worse overall survival (OS; p=0.009) children, but not progression-free (PFS; p=0.106). With an age cut-off at 18 years, no difference found. Also adolescents alone (16-20 years) had OS (p=0.003) whereas ≥21 (n=12 adults PFS/OS data) progression/relapse occurred. Only one adult died therapy-related complications. WNT-MB tumors harboring (24/133, 18.1%) significant PFS (p=0.001), which also individually (p=0.004, resp. p=0.017). Gains OTX2 locus on chromosome 14q 40.2% (35/87) samples independent associated poor (p=0.034, p=0.016). Individual analyses gains within groups only (p=0.012). Multivariate Cox regression for identified both alterations, For OS, multivariate older Conclusion Our suggest that adolescent those carrying or - are higher risk relapse. Eligibility these therapy de-escalation trials needs be debated.