Subgroup-specific prognostic implications of TP53 mutation in medulloblastoma

Abstract

Purpose: Reports detailing the prognostic impact of TP53 mutations in medulloblastoma offer conflicting conclusions. We resolve this issue through the inclusion of molecular subgroup profiles.

Patients and methods: We determined subgroup affiliation, TP53 mutation status, and clinical outcome in a discovery cohort of 397 medulloblastomas. We subsequently validated our results on an independent cohort of 156 medulloblastomas.

Results: TP53 mutations are enriched in wingless (WNT; 16%) and sonic hedgehog (SHH; 21%) medulloblastomas and are virtually absent in subgroups 3 and 4 tumors (P < .001). Patients with SHH/TP53 mutant tumors are almost exclusively between ages 5 and 18 years, dramatically different from the general SHH distribution (P < .001). Children with SHH/TP53 mutant tumors harbor 56% germline TP53 mutations, which are not observed in children with WNT/TP53 mutant tumors. Five-year overall survival (OS; ± SE) was 41% ± 9% and 81% ± 5% for patients with SHH medulloblastomas with and without TP53 mutations, respectively (P < .001). Furthermore, TP53 mutations accounted for 72% of deaths in children older than 5 years with SHH medulloblastomas. In contrast, 5-year OS rates were 90% ± 9% and 97% ± 3% for patients with WNT tumors with and without TP53 mutations (P = .21). Multivariate analysis revealed that TP53 status was the most important risk factor for SHH medulloblastoma. Survival rates in the validation cohort mimicked the discovery results, revealing that poor survival of TP53 mutations is restricted to patients with SHH medulloblastomas (P = .012) and not WNT tumors.

Conclusion: Subgroup-specific analysis reconciles prior conflicting publications and confirms that TP53 mutations are enriched among SHH medulloblastomas, in which they portend poor outcome and account for a large proportion of treatment failures in these patients.

Fig 1.

Kaplan-Meier estimates of overall survival for study patients by group. (A) All discovery cohort patients by TP53 mutations. Blue line, TP53 wild type, wingless (WNT) group; gold line TP53 mutant, sonic hedgehog (SHH) group. (B) TP53-mutant tumors stratified by subgroup analysis. Blue line, WNT group; gold line, SHH group. (C) Blue line, TP53 wild type, WNT group; gold line, TP53 mutant, SHH group. (D) WNT tumors from the discovery cohort. Blue line, TP53 wild type, WNT group; gold line, TP53 mutant, SHH group. (E) SHH tumors from the validation cohort. Blue line, TP53 wild type, WNT group; gold line, TP53 mutant, SHH group. (F) WNT tumors from the validation cohort. Blue line, TP53 wild type, WNT group; gold line, TP53 mutant, SHH group.

Fig 2.

Characteristics of TP53 mutation in medulloblastoma. (A) Percentage of TP53 mutations in medulloblastoma subgroups; (B) Age distribution of sonic hedgehog (SHH) medullablastoma according to TP53 status. (C) Distribution of TP53 mutations according to functional domains. WNT, wingless.

Fig 3.

Risk stratification for patients with medulloblastoma based on molecular subgroups and TP53 status. SHH, sonic hedgehog; WNT, wingless; WT, wild type.

Fig A1.

Survival estimates for children with sonic hedgehog (SHH)/TP53-mutant tumors when germline TP53 status was available (n = 16).

Fig A2.

Kaplan-Meier estimates of overall survival for children and infants by group. (A) Sonic hedgehog (SHH) tumors from the discovery cohort. (B) Wingless (WNT) tumors from the discovery cohort.