Novel molecular subgroups for clinical classification and outcome prediction in childhood medulloblastoma: a cohort study

Abstract

SummaryBackgroundInternational consensus recognises four medulloblastoma molecular subgroups: WNT (MBWNT), SHH (MBSHH), group 3 (MBGrp3), and group 4 (MBGrp4), each defined by their characteristic genome-wide transcriptomic and DNA methylomic profiles. These subgroups have distinct clinicopathological and molecular features, and underpin current disease subclassification and initial subgroup-directed therapies that are underway in clinical trials. However, substantial biological heterogeneity and differences in survival are apparent within each subgroup, which remain to be resolved. We aimed to investigate whether additional molecular subgroups exist within childhood medulloblastoma and whether these could be used to improve disease subclassification and prognosis predictions.MethodsIn this retrospective cohort study, we assessed 428 primary medulloblastoma samples collected from UK Children's Cancer and Leukaemia Group (CCLG) treatment centres (UK), collaborating European institutions, and the UKCCSG-SIOP-PNET3 European clinical trial. An independent validation cohort (n=276) of archival tumour samples was also analysed. We analysed samples from patients with childhood medulloblastoma who were aged 0–16 years at diagnosis, and had central review of pathology and comprehensive clinical data. We did comprehensive molecular profiling, including DNA methylation microarray analysis, and did unsupervised class discovery of test and validation cohorts to identify consensus primary molecular subgroups and characterise their clinical and biological significance. We modelled survival of patients aged 3–16 years in patients (n=215) who had craniospinal irradiation and had been treated with a curative intent.FindingsSeven robust and reproducible primary molecular subgroups of childhood medulloblastoma were identified. MBWNT remained unchanged and each remaining consensus subgroup was split in two. MBSHH was split into age-dependent subgroups corresponding to infant (<4·3 years; MBSHH-Infant; n=65) and childhood patients (≥4·3 years; MBSHH-Child; n=38). MBGrp3 and MBGrp4 were each split into high-risk (MBGrp3-HR [n=65] and MBGrp4-HR [n=85]) and low-risk (MBGrp3-LR [n=50] and MBGrp4-LR [n=73]) subgroups. These biological subgroups were validated in the independent cohort. We identified features of the seven subgroups that were predictive of outcome. Cross-validated subgroup-dependent survival models, incorporating these novel subgroups along with secondary clinicopathological and molecular features and established disease risk-factors, outperformed existing disease risk-stratification schemes. These subgroup-dependent models stratified patients into four clinical risk groups for 5-year progression-free survival: favourable risk (54 [25%] of 215 patients; 91% survival [95% CI 82–100]); standard risk (50 [23%] patients; 81% survival [70–94]); high-risk (82 [38%] patients; 42% survival [31–56]); and very high-risk (29 [13%] patients; 28% survival [14–56]).InterpretationThe discovery of seven novel, clinically significant subgrou...

NRL and CRX Define Photoreceptor Identity and Reveal Subgroup-Specific Dependencies in Medulloblastoma

“…Surprisingly, although Group 3 MBs are often generalized as a subgroup defined by aberrant MYC expression across the subgroup (Roussel and Robinson, 2013), we observed an inverse correlation between the photoreceptor program defined by NRL/CRX activity and gene sets associated with MYC family amplification. This observation is consistent with the concept of intra-subgroup heterogeneity in MB (Cavalli et al, 2017; Northcott et al, 2017; Schwalbe et al, 2017) and thus, our data further support that Group 3 MBs are comprised of molecularly and phenotypically distinct subtypes. Importantly, we showed that NRL/CRX are not only responsible for regulating the photoreceptor program in Group 3, but are also required for maintenance of the malignant phenotype of these tumors.…”

“…This recognized overlap may explain why a small fraction of Group 4 MBs exhibit high levels of NRL / CRX . The recent demonstration of intragroup heterogeneity (Cavalli et al, 2017; Northcott et al, 2017; Schwalbe et al, 2017) further contextualizes these observations, as we noted high NRL/CRX expression mainly in pure Group 3 subtypes (namely subtypes II and III) and to a lesser extent in mixed subtypes (namely NRL in subtype I). shRNA-mediated perturbation of NRL and subsequent transcriptional analysis of targeted cells validated the computational inferences we derived from primary enhancer/transcriptome datasets, confirming that NRL controls the photoreceptor program and a subset of Group 3 signature genes.…”

“…Recent genomic studies have further defined molecular heterogeneity within consensus MB subgroups, reporting a varying degree of discrete ‘subtypes’ within subgroups (Cavalli et al, 2017; Northcott et al, 2017; Schwalbe et al, 2017). To determine whether the photoreceptor program defined by NRL and CRX is linked to particular subtypes, we analyzed NRL and CRX expression according to the Group 3/Group 4 substructure we recently reported for a large series of MBs profiled by DNA methylation array (Northcott et al, 2017).…”

Seltene Tumordispositionssyndrome mit Manifestation im Kindesalter

“…Neben den klassischen histologischen Kategorien führte die molekulargenetische Charakterisierung von Medulloblastomen zur Definition von vier distinkten Subgruppen [33,34], die in Zukunft weitere Differenzierungen erfahren werden [35][36][37]. Ziel dieser Klassifizierungen ist die Verbesserung der risikoadaptierten Therapie, das heißt die Steigerung der Heilungsrate bei Minimierung unerwünschter therapieassoziierter Langzeitfolgen (zum Beispiel intellektuelle und neuroendokrine Beeinträchtigun-gen) sowie die Identifikation aberranter Signaltransduktionswege als Angriffspunkt zielgerichteter Therapieansätze [33].…”

“…Das Gorlin-Syndrom (Basalzellnävus-Syndrom, Gorlin-Goltz-Syndrom, nävoi-des Basalzellkarzinom-Syndrom) ist durch multiple Basalzellkarzinome vor dem 30 [35].…”