Molecular and clinical heterogeneity within MYC-family amplified medulloblastoma is associated with survival outcomes: A multicenter cohort study

Abstract

Background: MYC/MYCN are the most frequent oncogene amplifications in medulloblastoma (MB) and its primary biomarkers of high-risk (HR) disease. However, while many patients' MYC(N)-amplified tumors are treatment-refractory, some achieve long-term survival. We therefore investigated clinicobiological heterogeneity within MYC(N)-amplified MB and determined its relevance for improved disease management.

Methods: We characterized the clinical and molecular correlates of MYC- (MYC-MB; n = 64) and MYCN-amplified MBs (MYCN-MB; n = 95), drawn from >1600 diagnostic cases.

Results: Most MYC-MBs were molecular group 3 (46/58; 79% assessable) and aged ≥3 years at diagnosis (44/64 [69%]). We identified a "canonical" very high-risk (VHR) MYC-amplified group (n = 51/62; 82%) with dismal survival irrespective of treatment (11% 5-year progression-free survival [PFS]), defined by co-occurrence with ≥1 additional established risk factor(s) (subtotal surgical-resection [STR], metastatic disease, LCA pathology), and commonly group 3/4 subgroup 2 with a high proportion of amplified cells. The majority of remaining noncanonical MYC-MBs survived (i.e. non-group 3/group 3 without other risk features; 11/62 (18%); 61% 5-year PFS). MYCN survival was primarily related to molecular group; MYCN-amplified SHH MB, and group 3/4 MB with additional risk factors, respectively defined VHR and HR groups (VHR, 39% [35/89]; 20% 5-year PFS/HR, 33% [29/89]; 46% 5-year PFS). Twenty-two out of 35 assessable MYCN-amplified SHH tumors harbored TP53 mutations; 9/12 (75%) with data were germline. MYCN-amplified group 3/4 MB with no other risk factors (28%; 25/89) had 70% 5-year PFS.

Conclusions: MYC(N)-amplified MB displays significant clinicobiological heterogeneity. Diagnostics incorporating molecular groups, subgroups, and clinical factors enable their risk assessment. VHR "canonical" MYC tumors are essentially incurable and SHH-MYCN-amplified MBs fare extremely poorly (20% survival at 5 years); both require urgent development of alternative treatment strategies. Conventional risk-adapted therapies are appropriate for more responsive groups, such as noncanonical MYC and non-SHH-MYCN MB.

Keywords: MYC amplification; MYCN amplification; medulloblastoma; survival.

Figure 1.

Clinicopathological and molecular features of MYC-MB and MYCN-MB. (A) Interphase fluorescence in situ hybridization (iFISH) of a group 3 tumor showing high levels of MYC amplification (green) vs centromeric control (red) in the majority of cells. (B, C) Example of a MYC-amplified group 4 tumor with a mixture of MYC-amplified, MYC gained and normal cells at 40× and 100× magnification. Clinical, molecular, and cytogenetic features are shown for MYC-MB (D) and MYCN-MB (G), arranged by molecular group. Groups (SHH, red; group 3, yellow; group 4, green; unknown, gray) and subgroups are colored by convention. Missing data are shown in gray. Factors with significant enrichment in specific molecular groups are shown in bold text (<.05, Fisher’s Exact test). The relationship between amplified cell fraction and molecular group is shown for MYC-MB (E) and MYCN-MB (H). Age distribution is shown for MYC-MB (F) and MYCN-MB (I). For molecular groups with few members, individual data points are shown.

Figure 2.

Differential patterns of chromothripsis and fusion transcripts within MYC-MB and MYCN-MB cohorts. Type and frequency of RNA fusion transcripts in (A) MYCN and (B) MYC-amplified tumors with molecular group, subgroup, chromothriptic chromosomes, and TP53 mutated status indicated. Missing data are shown by an empty cell. Chromosomal distribution of chromothripsis is shown for 8 individual MYCN-amplified tumors (C) and 6 individual MYC-amplified tumors (D), with CN profiles from SNP6 array data (each tumor individually colored within each cohort). Circos plots show the distribution of RNA fusion transcripts in (E) MYCN (n = 15, data combined) and (F) MYC-amplified tumors (n = 12, data combined); interchromosomal fusions shown in blue and intrachromosomal fusions shown in red.

Figure 3.

Survival of patients with MYC-amplified tumors by clinical and molecular risk features. (A–F) Kaplan-Meier plots and at-risk tables are shown for MYC-amplified tumors. Where appropriate, the molecular group is indicated by filled circles adjacent to censor points for survivors with PFS ≥ 4 years; the molecular group is shown on inset pie charts. Certain MYC-amplified tumors lacked molecular group information and were omitted from the pie charts. Molecular group colors: SHH, red; group 3, yellow; group 4, green; N/A, gray.

Figure 4.

Survival of patients with MYCN-amplified tumors by clinical and molecular risk features. (A–F) Kaplan-Meier plots and at-risk tables are shown for MYCN-amplified tumors. Where appropriate, the molecular group is indicated by filled circles adjacent to censor points for survivors with PFS ≥ 4 years; the molecular group is shown on inset pie charts. Certain MYCN-amplified tumors lacked molecular group information and were omitted from the pie charts. Molecular group colors: SHH, red; group 3, yellow; group 4, green; N/A, gray.

Figure 5.

Cranio-spinal irradiation is ineffective in MYC-amplified tumors with additional established risk features. (A) Survival of MYC-amplified tumors by receipt of radiotherapy. (B) Survival of nonmetastatic, gross-totally resected, non-LCA MYC-amplified tumors, stratified by receipt of radiation. (C) Survival of MYC-amplified tumors with positivity for one or more HR features in addition to MYC amplification, stratified by receipt of radiation. Where appropriate, the molecular group is indicated by filled circles adjacent to censor points for survivors with PFS ≥ 4 years; the molecular group is shown as inset pie charts; certain MYC-amplified tumors lacked molecular group information and were omitted from pie charts. (D) Venn diagram summarizes co-occurrence of HR disease features in MYC-MB. Molecular group colors: SHH, red; group 3, yellow; group 4, green; N/A, gray.

Figure 6.

Treatment stratification and survival groups within MYC-MB and MYCN-MB. (A, C) Suggested stratification for MYC-MB and MYCN-MB. (B, D) Risk stratification identifies VHR patient groups and groups compatible with longer-term survival. For each treatment group, Kaplan-Meier plots with risk tables are shown, with insets showing additional features of each group—the proportion of amplified cells, molecular group, and subgroup. SR, standard risk; HR, high risk; VHR, very high risk.