Genetic alterations of TP53 and OTX2 indicate increased risk of relapse in WNT medulloblastomas

Abstract

This study aimed to re-evaluate the prognostic impact of TP53 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 CTNNB1, APC, and TP53 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. CTNNB1 mutations were present in 92.2%, and APC mutations in 6.8% of samples. One CTNNB1 wild-type tumor gained WNT activation due to homozygous FBXW7 deletion. Monosomy 6 was present in 78.6%, and more frequent in children than adults. 16.1% of tumor samples showed TP53 mutations, of those 60% with nuclear positivity for the p53 protein. Loss of heterozygosity at the TP53 locus (chromosome 17p13.1) was found in 40.7% (11/27) of TP53 mutant tumor samples and in 12.6% of TP53 wild-type cases (13/103). Patients with tumors harboring TP53 mutations showed significant worse progression-free survival (PFS; 5-year-PFS 68% versus 93%, p = 0.001), and were enriched for chromosomes 17p (p = 0.001), 10, and 13 losses. Gains of OTX2 (14q22.3) occurred in 38.9% of samples and were associated with poor PFS and OS (5-year-PFS 72% versus 93%, p = 0.017 resp. 5-year-OS 83% versus 97%, p = 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 TP53 mutations or OTX2 gains (58.1%) are at higher risk of relapse. Eligibility of these patients for therapy de-escalation trials needs to be debated.

Genetic alterations of TP53 and OTX2 indicate increased risk of relapse in WNT medulloblastomas: “it’s a numbers game”—implications for WNT medulloblastoma dose-reduction clinical trials

“…A recent study however reinvigorated interest in the prognostic relevance of TP53 mutations in WNT medulloblastoma, reporting that four of five (80%) relapsed patients had TP53 mutations [ 7 ]. Goschzik and colleagues identified TP53 mutations in 16.1% (30/186) of WNT samples and support these findings, with six of eleven (54.5%) patients who relapsed harboring a TP53 mutation (Table 2 ) [ 3 ]. The novel finding of OTX2 oncogene gain in 42/108 (39%) WNT medulloblastomas was identified using molecular inversion probe (MIP) array technology and was associated with significantly worse progression free survival (PFS) and OS [ 3 ].…”

“…Goschzik and colleagues identified TP53 mutations in 16.1% (30/186) of WNT samples and support these findings, with six of eleven (54.5%) patients who relapsed harboring a TP53 mutation (Table 2 ) [ 3 ]. The novel finding of OTX2 oncogene gain in 42/108 (39%) WNT medulloblastomas was identified using molecular inversion probe (MIP) array technology and was associated with significantly worse progression free survival (PFS) and OS [ 3 ]. Overall, all 11 patients who relapsed harbored either a TP53 mutation (3/11 (27%)) or OTX2 gain [(5/11 (45%)) or both (3/11 (27%)] (Table 2 ).…”

“…Goschzik and colleagues [ 3 ] identified TP53 mutation and OTX2 gain as independent prognostic markers in WNT medulloblastoma patients. Findings were derived from 191 (of which 120 were clinically annotated) pediatric and adult retrospective WNT medulloblastoma cases in the German HIT-2000 trial and HIT registries.…”

Targeting of the ELR+CXCL/CXCR1/2 Pathway Is a Relevant Strategy for the Treatment of Paediatric Medulloblastomas

“…P53 mutation is virtually absent from WNT MB [ 15 ]. This mutation appears in the three other groups and may account for a significant number of recurrent and fatal average-risk medulloblastomas [ 16 ].…”

“…The aggressiveness of the treatments leads to significant short- and long-term side effects such as neurocognitive and functional deficits [ 1 , 2 ]. Relapses are usually fatal, albeit very rare in the WNT MB subgroup [ 16 ].…”