Interrogating molecular data for medulloblastoma risk stratification
Authors: Elisabetta Ferretti, Agnese Po
Journal: The Lancet Oncology (2018)

Medulloblastoma is the most common malignant paediatric brain tumour, with an incidence between 2·34 and 5·96 per million population.1Smoll NR Drummond KJ The incidence of medulloblastomas and primitive neurectodermal tumours in adults and children.J Clin Neurosci. 2012; 19: 1541-1544Summary Full Text Full Text PDF PubMed Scopus (138) Google Scholar Early studies on medulloblastoma biology were largely inconclusive because of its molecular heterogeneity and the small size of the cohorts analysed. By contrast, more recent studies, based on a large number of internationally collected cases, have produced a deeper understanding of the molecular events that characterise medulloblastoma. Indeed, on the basis of gene expression, genetic aberrations, and DNA methylation, medulloblastoma is now classified into several molecular subgroups.2Northcott PA Shih DJ Peacock J et al.Subgroup-specific structural variation across 1000 medulloblastoma genomes.Nature. 2012; 488: 49-56Crossref PubMed Scopus (628) Google Scholar, 3Schwalbe EC Lindsey JC Nakjang S et al.Novel molecular subgroups for clinical classification and outcome prediction in childhood medulloblastoma: a cohort study.Lancet Oncol. 2017; 18: 958-971Summary Full Text Full Text PDF PubMed Scopus (300) Google Scholar, 4Northcott PA Buchhalter I Morrissy AS et al.The whole-genome landscape of medulloblastoma subtypes.Nature. 2017; 547: 311-317Crossref PubMed Scopus (556) Google Scholar, 5Cavalli FMG Remke M Rampasek L et al.Intertumoral heterogeneity within medulloblastoma subgroups.Cancer Cell. 2017; 31: 737-754Summary Full Text Full Text PDF PubMed Scopus (598) Google Scholar The 2016 WHO Classification of Tumors of the Central Nervous System6Louis DN Perry A Reifenberger G et al.The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary.Acta Neuropathol. 2016; 131: 803-820Crossref PubMed Scopus (9342) Google Scholar combines molecular and histological features for an innovative integrated diagnosis, thus allowing stratification of patients into four prognostic risk categories: favourable, standard, high, and very high risk.3Schwalbe EC Lindsey JC Nakjang S et al.Novel molecular subgroups for clinical classification and outcome prediction in childhood medulloblastoma: a cohort study.Lancet Oncol. 2017; 18: 958-971Summary Full Text Full Text PDF PubMed Scopus (300) Google Scholar The standard-risk medulloblastoma category is heterogeneous, comprising 50–60% of patients with medulloblastoma and encompassing SHH-activated TP53wild-type and groups 3 and 4, in the absence of high-risk features (ie, MYC amplification, anaplastic histology, or metastasis at diagnosis). The therapeutic regimen for standard-risk medulloblastoma includes radiotherapy followed by chemotherapy, with a 5-year progression-free survival of 75–85%. However, surviving patients have a heavy burden of long-term severe endocrine and neurological sequelae.7Robinson GW Rudneva VA Buchhalter I et al.Risk-adapted therapy for young children with medulloblastoma (SJYC07): therapeutic and molecular outcomes from a multicentre, phase 2 trial.Lancet Oncol. 2018; 19: 768-784Summary Full Text Full Text PDF PubMed Scopus (129) Google Scholar Therefore, there is urgent need for identification of patients with good prognosis who could benefit from therapy de-escalation, which maintains curative potential while minimising adverse effects. To this aim, the pan-European SIOP PNET 5 clinical trial (NCT02066220) is testing a reduced treatment scheme for the favourable-risk category, which consists of patients with WNT-positive medulloblastoma younger than 16 years. Unfortunately, patients meeting these inclusion criteria account for only roughly 8% of all medulloblastomas. In The Lancet Oncology, Tobias Goschzik and colleagues8Goschzik T Schwalbe EC Hicks D et al.Prognostic effect of whole chromosomal aberration signatures in standard-risk non-WNT/non-SHH medulloblastoma: a retrospective, molecular analysis of the HIT-SIOP PNET 4 trial.Lancet Oncol. 2018; (published online Nov 1.)http://dx.doi.org/10.1016/S1470-2045(18)30532-1Summary Full Text Full Text PDF PubMed Scopus (47) Google Scholar did a whole chromosomal aberration analysis of standard-risk medulloblastoma and investigated the association between molecular features and progression-free survival, taking advantage of available samples from the completed pan-European HIT-SIOP PNET 4 trial,9Lannering B Rutkowski S Doz F et al.Hyperfractionated versus conventional radiotherapy followed by chemotherapy in standard-risk medulloblastoma: results from the randomized multicenter HIT-SIOP PNET 4 trial.J Clin Oncol. 2012; 30: 3187-3193Crossref PubMed Scopus (209) Google Scholar with the intent of improving prognosis prediction. They found a new prognostic genetic biomarker signature—defined as at least two events among chromosome 7 gain, chromosome 8 loss, and chromosome 11 loss—associated with good prognosis (5-year progression-free survival of 100% in the HIT-SIOP PNET 4 cohort) in patients with non-WNT/non-SHH standard-risk medulloblastoma. The identified risk stratification scheme was a more solid model with respect to previous ones, allowing reallocation of a subset of patients with standard-risk medulloblastoma into a favourable-risk group. Crucially, the proposed risk stratification applies to 51% of standard-risk medulloblastomas, and thus to 25–30% of all patients with medulloblastoma. Consequently, these findings increase the number of patients who could be enrolled for therapy de-escalation in future clinical trials. As mentioned, methylation and gene expression analyses have produced an immense amount of important data that provided deep insight into the molecular events that underlie pathogenesis and laid the foundation for the development of targeted therapies.2Northcott PA Shih DJ Peacock J et al.Subgroup-specific structural variation across 1000 medulloblastoma genomes.Nature. 2012; 488: 49-56Crossref PubMed Scopus (628) Google Scholar, 3Schwalbe EC Lindsey JC Nakjang S et al.Novel molecular subgroups for clinical classification and outcome prediction in childhood medulloblastoma: a cohort study.Lancet Oncol. 2017; 18: 958-971Summary Full Text Full Text PDF PubMed Scopus (300) Google Scholar, 4Northcott PA Buchhalter I Morrissy AS et al.The whole-genome landscape of medulloblastoma subtypes.Nature. 2017; 547: 311-317Crossref PubMed Scopus (556) Google Scholar, 5Cavalli FMG Remke M Rampasek L et al.Intertumoral heterogeneity within medulloblastoma subgroups.Cancer Cell. 2017; 31: 737-754Summary Full Text Full Text PDF PubMed Scopus (598) Google Scholar Data from genomic analyses are in clinical use for patient risk stratification, with molecular genomic biomarkers (ie, TP53 mutational status and CMYC or NMYC amplification) being an integral element of the latest WHO classification.6Louis DN Perry A Reifenberger G et al.The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary.Acta Neuropathol. 2016; 131: 803-820Crossref PubMed Scopus (9342) Google Scholar Goschzik and colleagues generated a whole chromosomal aberration signature that can group patients who share the same prognosis, even though they are classified in different molecular subgroups.8Goschzik T Schwalbe EC Hicks D et al.Prognostic effect of whole chromosomal aberration signatures in standard-risk non-WNT/non-SHH medulloblastoma: a retrospective, molecular analysis of the HIT-SIOP PNET 4 trial.Lancet Oncol. 2018; (published online Nov 1.)http://dx.doi.org/10.1016/S1470-2045(18)30532-1Summary Full Text Full Text PDF PubMed Scopus (47) Google Scholar Indeed, the identified whole chromosomal aberration signature-positive class included patients with MBGrp4-LowRisk3Schwalbe EC Lindsey JC Nakjang S et al.Novel molecular subgroups for clinical classification and outcome prediction in childhood medulloblastoma: a cohort study.Lancet Oncol. 2017; 18: 958-971Summary Full Text Full Text PDF PubMed Scopus (300) Google Scholar and Group3 and Group4 subgroups VI and VII.4Northcott PA Buchhalter I Morrissy AS et al.The whole-genome landscape of medulloblastoma subtypes.Nature. 2017; 547: 311-317Crossref PubMed Scopus (556) Google Scholar Important points that strengthen the reported results8Goschzik T Schwalbe EC Hicks D et al.Prognostic effect of whole chromosomal aberration signatures in standard-risk non-WNT/non-SHH medulloblastoma: a retrospective, molecular analysis of the HIT-SIOP PNET 4 trial.Lancet Oncol. 2018; (published online Nov 1.)http://dx.doi.org/10.1016/S1470-2045(18)30532-1Summary Full Text Full Text PDF PubMed Scopus (47) Google Scholar are clinical evidence of the proven utility of molecular data investigation, use of a strictly defined and well-characterised population (HIT-SIOP PNET 4 trial cohort) for generation of the data, and validation of the proposed model in an independent patient cohort with matched demographic characteristics. Another class of molecular biomarkers that should be considered for implementation of stratification risk models in medulloblastoma is non-coding RNAs. microRNAs and long non-coding RNAs have been shown to be important regulators of medulloblastoma biology, and could represent valuable biomarkers for risk stratification and targeted therapy.10Laneve P Po A Favia A et al.The long noncoding RNA linc-NeD125 controls the expression of medulloblastoma driver genes by microRNA sponge activity.Oncotarget. 2017; 8: 31 003-31 015Crossref Scopus (34) Google Scholar In conclusion, this study8Goschzik T Schwalbe EC Hicks D et al.Prognostic effect of whole chromosomal aberration signatures in standard-risk non-WNT/non-SHH medulloblastoma: a retrospective, molecular analysis of the HIT-SIOP PNET 4 trial.Lancet Oncol. 2018; (published online Nov 1.)http://dx.doi.org/10.1016/S1470-2045(18)30532-1Summary Full Text Full Text PDF PubMed Scopus (47) Google Scholar provides a tool for immediate clinical application. Although these results require validation in a controlled multicentre study, they set the foundation that is needed to improve genomic patient characterisation for more accurate risk stratification in routine clinical settings. We declare no competing interests. Prognostic effect of whole chromosomal aberration signatures in standard-risk, non-WNT/non-SHH medulloblastoma: a retrospective, molecular analysis of the HIT-SIOP PNET 4 trialWe define a whole chromosomal signature that allows the assignment of non-WNT/non-SHH medulloblastoma patients normally classified as standard-risk into favourable-risk and high-risk categories. In addition to patients younger than 16 years with WNT tumours, patients with non-WNT/non-SHH tumours with our defined whole chromosomal aberration signature and patients with SHH-TP53wild-type tumours should be considered for therapy de-escalation in future biomarker-driven, risk-adapted clinical trials. Full-Text PDF Open Access