Medulloblastoma (MB) is the most common malignant brain tumor of childhood. Although overall cure rates of ∼70% are now achieved, advances in our biological understanding of the disease will be essential for future improvements in outcome, through improved disease risk stratification and molecular therapeutic strategies. Mutations of TP53 are reported in ∼10% of MBs and have recently been reported to be associated with universally poor disease outcome (Tabori et al. (2010). J Clin Oncol 28: 1345-50), however, this relationship now requires validation in further cohorts. Additionally, there is now strong evidence that MB comprises a series of distinct molecular sub-types with characteristic molecular defects, transcriptional profiles and disease behaviour. WNT subgroup tumors (15% of cases) display activation of the WNT pathway and are associated with a favorable prognosis (>90% survival), while sonic hedgehog signalling pathway (SHH) activated tumors (∼25% of cases) also form a distinct subgroup. We therefore sought to analyse the frequency of TP53 mutations in these major MB molecular subgroups and investigate their impact on disease prognosis.
A cohort of 50 MBs was selected to include representatives of all major established clinicopathological groups. WNT subgroup cases (n=15) were selected for inclusion by the presence of CTNNB1 mutations and chromosome 6 defects, while SHH subgroup cases (n=12) were identified by their characteristic transcriptional profiles. TP53 mutations were investigated by PCR-based direct DNA sequence analysis of exons 4-9. TP53 missense mutations were observed in 5 cases (10%); all were in non-infant, non-metastatic cases, classified clinically as ‘standard risk’. On review, one was identified as a germline mutation (Li-Fraumeni syndrome: LFS), whilst all others were somatic mutations in sporadic tumors. All 4 cases with a somatic TP53 mutation achieved a durable remission of between 5.6-11.1 years, while the LFS case relapsed and died within 1.1 years. Evidence of TP53 mutations were found in all MB subgroups, but mutations appeared enriched in the WNT subgroup (3/15 (20%) WNT tumors; 1/12 (8%) SHH tumors (LFS case); 1/23 (4%) non-WNT/SHH tumors).
These data suggest that the prognostic significance of TP53 mutations in MB is dependent on the molecular and clinical context in which they arise. Whilst a poor outcome was observed for the TP53 mutation-associated LFS case, our findings demonstrate that TP53 mutation is not associated with a universally poor prognosis, and indicate TP53 mutations are enriched in the WNT subgroup, where subgroup membership remains the overriding favorable prognostic determinant.