NATURE REVIEWS | NEUROLOGY VOLUME 10 | JANUARY 2014 | 5

NEWS & VIEWSNEURO-ONCOLOGY

Stability of medulloblastoma subgroups at tumour recurrenceJacques Grill and Christelle Dufour

Medulloblastomas can be categorized into four molecular subgroups. A new report shows, for the first time, that these tumours remain in the same subgroup at relapse, and the molecular subgroup influences the pattern of relapse. These findings indicate that this developmentally defined classification is robust, although its relationship to prognosis remains uncertain.Grill, J. & Dufour, C. Nat. Rev. Neurol. 10, 5–6 (2014); published online 10 December 2013; doi:10.1038/nrneurol.2013.256

Recurrent medulloblastoma is a considerable therapeutic challenge in paediatric neuro-oncology: rescue therapy is effective only in children who did not receive radiotherapy as part of their first-line treatment.1 A new study by Vijay Ramaswamy and colleagues,2 which brings together the largest cohort of patients with recurrent medulloblastoma to date, has generated two very important findings to consider in the context of patient management. First, the authors show that recurrent tumours belong to the same bio-logical subgroup as the original tumour and, second, they show that the pattern of recurrence is subgroup-dependent.3

Medulloblastomas have been reprodu-cibly clustered into four subclasses: group 1 tumours with activating mutations in the sonic hedgehog (SHH) pathway, group 2 tumours driven by WNT activation (most frequently via mutations in the β-catenin gene), group 3 tumours with Myc amplifi-cation and alterations in TGFβ-OTX2 sig-nalling, and group 4 tumours, which have a neuronal gene expression signature. Group 1 and group 2 tumours are well-delineated in terms of oncogenesis, whereas group 3 and group 4 tumours are less clearly defined from a biological point of view.

Using a nanoStr ing-based assay, Ramaswamy et al. performed molecular subgrouping in three cohorts of patients with recurrent medulloblastoma: a dis-covery cohort (cohort 1, n = 30) and two validation cohorts (cohort 2, n = 77 and cohort 3, n = 96).2 In a total of 34 cases from cohorts 1 and 2, tissue was available both from the original tumour and at recurrence. In all these cases, the molecular subgroup was unchanged at recurrence—a finding

that was validated in a further cohort of 17 patients. The researchers found that group 3 and group 4 tumours mostly exhibited meta-static recurrence, whereas the vast major-ity of group 1 tumours recurred locally. In cohorts 1 and 2, the group 4 subtype was associated with significantly longer survival times after recurrence, but this finding could not be replicated in cohort 3.

If medulloblastomas do not change their subgroup at the time of relapse, we can speculate that subgroup-specific targeted therapies can be defined on the grounds of the initial biological work-up—a pragmatic approach that was taken into account in the ongoing trials of SHH inhibitors in these tumours. This phenomenon has not been found in all brain tumours; in glioblastoma,

for example, genetic subgroup affiliation can change at recurrence.4 For most medullo-blastoma subtypes, it is possible to assign a specific cell of origin—external granule layer progenitors for SHH-driven tumours, lower rhombic lip for WNT-driven tumours and postnatal cerebellar progenitor cells for group 3 tumours (Figure 1)—the gene expression and/or methylation profiles of which are likely to be conserved. By con-trast, glioblastoma tends to be defined by phenotypic traits rather than developmental origins. The greater intratumoural hetero-geneity, combining different molecular subtypes in the same tumour and evolu-tionary dynamics at the tumour level,5 could also account for the phenotypic switches encountered in glioblastoma.

Figure 1 | Medulloblastoma subgroups and recurrence patterns. At recurrence, the medulloblastoma does not change its subgroup. The main drivers of oncogenesis are indicated. WNT medulloblastomas (blue) originate from the rhombic lip. SHH medulloblastomas (red) originate from the external granular cell layer of the cerebellum. The origin of group 3 and group 4 medulloblastomas (yellow and green, respectively) has not been ascertained. WNT medulloblastomas rarely recur (indicated by a cross). SHH medulloblastomas recur mainly locally. Group 3 and group 4 medulloblastomas recur mainly with metastases. Abbreviation: SHH, sonic hedgehog.

Brainstem

Cerebellum

Fourthventricle

Unknowncell of origin

KDM6A/neuronal

Postnatal cerebellarprogenitor

TGFβ–OTX2/Myc

Externalgranule layer

SHH

Rhombiclip

WNT

Recur mainly with metastases

Recurmainlylocally

Rarelyrecur

Recurmainly withmetastases

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NEWS & VIEWS

As already shown in many cancers, it was anticipated that the biology of the medullo-blastoma would influence tumour progres-sion, since some of the earliest genomic studies showed that metastatic medullo-blastomas have different gene expres-sion signatures and patterns of molecular pathway activation from those observed in localized medulloblastomas.6 In the study by Ramaswamy et al.,2 the authors link the developmental origin under lying the sub-grouping with the pattern of relapse. If con-firmed prospectively in trial cohorts, this relationship would have important implica-tions for the refinement of subgroup-specific trial design in medulloblastomas.

Similar results have been shown in other paediatric tumours: in paediatric epen dymoma, for example, compari-son of recurrent tumours with the initial tumour has revealed different patterns of progression depending on the location—and, hence, the developmental origin—of the tumour.7 In this study, supratentorial epen dymomas exhibited overexpression of matrix remodel ling and motility genes compared with infratentorial tumours. This finding correlated with a higher invasive potential in supratentorial ependymoma, indicating that a larger margin should be used for the irradiation of these tumours than for  infratentorial ependymoma.

Owing to the relatively small number of cases studied by Ramaswamy et al.,2 the treat-ment effect might not have been properly assessable in some categories. SHH-driven medulloblastomas had a greater likelihood of local relapse than did the other subgroups, but these tumours are more frequently seen in younger children in whom radiotherapy is seldomly used. In epen dymoma, relapses are early and mainly local when the tumour is treated with chemo therapy only, while after local radiotherapy more metastatic recur-rences are observed and local recurrences are delayed.8 The results of the new study must, therefore, be confirmed in homogeneously treated patient cohorts.

A possible technical limitation of the Ramaswamy et  al. study is the use of nanoString targeted gene expression pro-filing, which assesses the expression of just 22 medulloblastoma signature genes.2 Accordingly, one could only conclude that

most of the gene expression patterns for the 22 genes observed at diagnosis are retained at relapse (although even among this small number of genes, some samples clearly had a different pattern). The reliability of the nanoString approach in predicting the bio-logical subgroup—that is, the specific gene expression profile—has only been assessed at diagnosis. Its performance at relapse, when the genetic diversity of the tumours beyond the 22 signature genes might have increased, cannot be predicted. What is missing from the analysis is a large subset of recurrent medulloblastoma samples ana lysed at relapse and clustered from the whole-genome gene expression point of view. It is likely that the basic four subclasses would be recapitulated, but additional sub-classes might emerge, as has been shown in diffuse intrinsic pontine gliomas, where two subclasses (mesenchymal and proneural) exist at diagnosis, and a third (proliferative) appears at autopsy.9,10

The study of tumour recurrence, as well as tumour biology during treatment, is an important aspect of the biological research that must be conducted to improve our knowledge of the oncogenesis and resistance to treatment of medulloblastoma and other neoplasms. This research has the potential to unravel numerous processes that are crucial for tumour development.

Programme Tumeurs Cérébrales, Department of Pediatric and Adolescent Oncology, Unité Mixte de Recherche 8203 du Centre National de la Recherche Scientifique, Institut Gustave Roussy, Université Paris XI, 114 rue Edouard Vaillant, 94805 Villejuif, France (J. Grill, C. Dufour).

Correspondence to: J. Grill jacques.grill@gustaveroussy.fr

Competing interestsThe authors declare no competing interests.

1. Grill, J. et al. Treatment of medulloblastoma with post-operative chemotherapy alone: an SFOP prospective trial in young children. Lancet Oncol. 6, 573–580 (2005).

2. Ramaswamy, V. et al. Recurrence patterns across medulloblastoma subgroups: an integrated clinical and molecular analysis. Lancet Oncol. 14, 1200–1207 (2013).

3. Northcott, P. A. et al. Subgroup-specific structural variation across 1,000 medulloblastoma genomes. Nature 488, 49–56 (2012).

4. Philips, H. S. et al. Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell 9, 157–173 (2006).

5. Sottoriva, A. et al. Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics. Proc. Natl Acad. Sci. USA 110, 4009–4014 (2013).

6. MacDonald, T. J. et al. Expression profiling of medulloblastoma: PDGFRA and the RAS/MAPK pathways as therapeutic targets for metastatic disease. Nat. Genet. 29, 143–152 (2001).

7. Peyre, M. et al. Portrait of ependymoma recurrence in children: biomarkers of tumor progression identified by dual-color microarray-based gene expression analysis. PLoS ONE 5, e12932 (2010).

8. Merchant, T. E. et al. Conformal radiotherapy after surgery for paediatric ependymoma: a prospective study. Lancet Oncol. 10, 258–266 (2009).

9. Paugh, B. S. et al. Genome-wide analyses identify recurrent amplifications of receptor tyrosine kinases and cell-cycle regulatory genes in diffuse intrinsic pontine glioma. J. Clin. Oncol. 29, 3999–4006 (2011).

10. Puget, S. et al. Mesenchymal transition and PDGFRA amplification/mutation are key distinct oncogenic events in pediatric diffuse intrinsic pontine gliomas. PLoS ONE 7, e30313 (2012).

‘‘…the authors link the developmental origin underlying the subgrouping with the pattern of relapse…’’

MOVEMENT DISORDERS

Tourette syndrome—beyond swearing and sex?Mary May Robertson

Gilles de la Tourette syndrome (GTS) is often perceived as the ‘swearing disease’, yet coprolalia affects only 10–15% of individuals with this condition. As highlighted in a new study, GTS has many phenotypes, some of which are sex-related. Could gender—that is, culturally established roles—also affect the phenotype?Robertson, M. M. Nat. Rev. Neurol. 10, 6–8 (2014); published online 3 December 2013; doi:10.1038/nrneurol.2013.248

In a study recently reported in the European Journal of Neurology, Rodgers et al. used latent class analysis (LCA) to identify sex-related and non-sex-related comorbidity

and psychopathological subtypes of Gilles de la Tourette syndrome (GTS) and other tic disorders in a community-based cohort.1 The researchers obtained data from the

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