Beschreibung:
<jats:title>Abstract</jats:title><jats:p>This study aimed to re-evaluate the prognostic impact of <jats:italic>TP53</jats:italic> mutations and to identify specific chromosomal aberrations as possible prognostic markers in WNT-activated medulloblastoma (WNT-MB). In a cohort of 191 patients with WNT-MBs, mutations in <jats:italic>CTNNB1</jats:italic>, <jats:italic>APC</jats:italic>, and <jats:italic>TP53</jats:italic> were analyzed by DNA sequencing. Chromosomal copy-number aberrations were assessed by molecular inversion probe technology (MIP), SNP6, or 850k methylation array hybridization. Prognostic impact was evaluated in 120 patients with follow-up data from the HIT2000 medulloblastoma trial or HIT registries. <jats:italic>CTNNB1</jats:italic> mutations were present in 92.2%, and <jats:italic>APC</jats:italic> mutations in 6.8% of samples. One <jats:italic>CTNNB1</jats:italic> wild-type tumor gained WNT activation due to homozygous <jats:italic>FBXW7</jats:italic> deletion. Monosomy 6 was present in 78.6%, and more frequent in children than adults. 16.1% of tumor samples showed <jats:italic>TP53</jats:italic> mutations, of those 60% with nuclear positivity for the p53 protein. Loss of heterozygosity at the <jats:italic>TP53</jats:italic> locus (chromosome 17p13.1) was found in 40.7% (11/27) of <jats:italic>TP53</jats:italic> mutant tumor samples and in 12.6% of <jats:italic>TP53</jats:italic> wild-type cases (13/103). Patients with tumors harboring <jats:italic>TP53</jats:italic> mutations showed significant worse progression-free survival (PFS; 5-year-PFS 68% versus 93%, <jats:italic>p</jats:italic> = 0.001), and were enriched for chromosomes 17p (<jats:italic>p</jats:italic> = 0.001), 10, and 13 losses. Gains of <jats:italic>OTX2</jats:italic> (14q22.3) occurred in 38.9% of samples and were associated with poor PFS and OS (5-year-PFS 72% versus 93%, <jats:italic>p</jats:italic> = 0.017 resp. 5-year-OS 83% versus 97%, <jats:italic>p</jats:italic> = 0.006). Multivariable Cox regression analysis for PFS/OS identified both genetic alterations as independent prognostic markers. Our data suggest that patients with WNT-MB carrying <jats:italic>TP53</jats:italic> mutations or <jats:italic>OTX2</jats:italic> gains (58.1%) are at higher risk of relapse. Eligibility of these patients for therapy de-escalation trials needs to be debated.</jats:p>