Cytogenetic prognostication within medulloblastoma subgroups

Abstract

Purpose: Medulloblastoma comprises four distinct molecular subgroups: WNT, SHH, Group 3, and Group 4. Current medulloblastoma protocols stratify patients based on clinical features: patient age, metastatic stage, extent of resection, and histologic variant. Stark prognostic and genetic differences among the four subgroups suggest that subgroup-specific molecular biomarkers could improve patient prognostication.

Patients and methods: Molecular biomarkers were identified from a discovery set of 673 medulloblastomas from 43 cities around the world. Combined risk stratification models were designed based on clinical and cytogenetic biomarkers identified by multivariable Cox proportional hazards analyses. Identified biomarkers were tested using fluorescent in situ hybridization (FISH) on a nonoverlapping medulloblastoma tissue microarray (n = 453), with subsequent validation of the risk stratification models.

Results: Subgroup information improves the predictive accuracy of a multivariable survival model compared with clinical biomarkers alone. Most previously published cytogenetic biomarkers are only prognostic within a single medulloblastoma subgroup. Profiling six FISH biomarkers (GLI2, MYC, chromosome 11 [chr11], chr14, 17p, and 17q) on formalin-fixed paraffin-embedded tissues, we can reliably and reproducibly identify very low-risk and very high-risk patients within SHH, Group 3, and Group 4 medulloblastomas.

Conclusion: Combining subgroup and cytogenetic biomarkers with established clinical biomarkers substantially improves patient prognostication, even in the context of heterogeneous clinical therapies. The prognostic significance of most molecular biomarkers is restricted to a specific subgroup. We have identified a small panel of cytogenetic biomarkers that reliably identifies very high-risk and very low-risk groups of patients, making it an excellent tool for selecting patients for therapy intensification and therapy de-escalation in future clinical trials.

Fig 1.

(A) Ten-year overall survival curves for WNT medulloblastoma by age group. (B) Overall survival curves for age groups within SHH and Group 4 subgroups (infant, age < 3 years; child, age 3 to < 16 years; adult, age ≥ 16 years). (C) Overall survival curves for metastatic status for SHH and Group 3 subgroups. Numbers below x-axis represent patients at risk of event; statistical significance evaluated using log-rank tests; hazard ratio (HR) estimates derived from Cox proportional hazards analyses.

Fig 2.

(A) Overall survival curves and frequency distribution of chromosome 6 (chr6) status across entire cohort. (B) Overall survival curves for chr6 status in WNT and non-WNT medulloblastomas. (C) Overall survival curves and frequency distribution of isochromosome 17q (iso17q) across entire cohort. Patients with broad gain or loss of chr17 excluded. (D) Overall survival curves for iso17q status in Group 3 and Group 4 subgroups. (E) Overall survival curves for chr10q status across entire cohort. HR, hazard ratio; NS, not significant.

Fig 3.

Clinical prognostication of patients with SHH medulloblastoma. (A) Risk stratification of SHH medulloblastomas by molecular and clinical prognostic markers. Decision tree, with events plot depicting status of molecular and clinical markers across risk groups below. (B) Overall survival curves for SHH risk groups. (C) Average time-dependent areas under the curve (AUCs) for risk groups stratified using only clinical or molecular markers or both. Risk stratification regimens applied to SHH and non-SHH medulloblastomas. ***P < .001 by Friedman rank sum tests. (D) Survival curves for SHH risk groups in validation cohort. Survival differences evaluated by log-rank tests; hazard ratio estimates derived from Cox proportional hazards analyses.

Fig 4.

Clinical prognostication of patients with Group 3 medulloblastoma. (A) Risk stratification of Group 3 medulloblastomas by molecular and clinical prognostic markers. Decision tree, with events plot depicting status of molecular and clinical markers across risk groups below. (B) Overall survival curves for Group 3 risk groups. (C) Average time-dependent areas under the curve (AUCs) for risk groups stratified using only clinical or molecular markers or both. Risk stratification regimens applied to Group 3 and non–Group 3 medulloblastomas. ***P < .001 by Friedman rank sum tests. (D) Survival curves for Group 3 risk groups in validation cohort. Survival differences evaluated by log-rank tests; hazard ratio estimates derived from Cox proportional hazards analyses. Iso, isochromosome.

Fig 5.

Clinical prognostication of patients with Group 4 medulloblastoma. (A) Risk stratification of Group 4 medulloblastomas by molecular and clinical prognostic markers. Decision tree, with events plot depicting status of molecular and clinical markers across risk groups below. (B) Overall survival curves for Group 4 risk groups. (C) Average time-dependent areas under the curve (AUCs) for risk groups stratified using only clinical or molecular markers or both. Risk stratification regimens applied to Group 4 and non–Group 4 medulloblastomas. ***P < .001 by Friedman rank sum tests. (D) Survival curves for Group 4 risk groups in validation cohort. Survival differences evaluated by log-rank tests; hazard ratio estimates derived from Cox proportional hazards analyses. Chr, chromosome.

Fig A1.

(A) Ten-year overall survival curves for WNT medulloblastoma by metastatic status. (B) Overall survival curves for age groups within Group 3 subgroup (infant, age < 3 years; child, age 3 to < 16 years). (C) Overall survival curves for metastatic status for Group 4 subgroup. Numbers below x-axis represent patients at risk of event; statistical significance evaluated by log-rank tests; hazard ratio (HR) estimates derived from Cox proportional hazards analyses. NS, not significant.

Fig A2.

Overall survival curves for chromosome 10q (chr10q) status in (A) SHH and (B) non-SHH medulloblastomas; survival differences evaluated by log-rank tests; hazard ratio (HR) estimates derived from Cox proportional hazards analyses. NS, not significant.

Fig A3.

Clinical prognostication of patients with SHH medulloblastoma. Overall survival curves for (A) GLI2 copy-number status, (B) MYCN copy-number status, (C) chromosome 14q (chr14q) status, and (D) chromothripsis status. HR, hazard ratio; NS, not significant.

Fig A4.

Clinical prognostication of patients with Group 3 medulloblastoma. Overall survival curves for (A) chromosome 17 (chr17) copy-number aberrations, (B) MYC copy-number status, and (C) chr8q status. HR, hazard ratio; iso, isochromosome; NS, not significant.

Fig A5.

Clinical prognostication of patients with Group 4 medulloblastoma. Overall survival curves for (A) chromosome 11 (chr11) status and whole chr17 status and (B) MYCN copy-number status. HR, hazard ratio; NS, not significant.