Robust molecular subgrouping and copy-number profiling of medulloblastoma from small amounts of archival tumour material using high-density DNA methylation arrays

Abstract

It is now clear that medulloblastoma (MB), one of the most clinically challenging paediatric brain tumours, is not a single disease entity. Rather, it comprises four distinct molecular subgroups (Wnt pathway activated (WNT), Sonic hedgehog pathway activated (SHH), and the less well-characterised Group 3 and Group 4) [7, 15], which are highly divergent in terms of their patient demographics, underlying biology, and survival outcomes [4, 6]. These subgroups are becoming increasingly important, not only for refining the discovery of prognostic markers or therapeutic targets, but also for the design of prospective clinical trials. Patients with WNT subgroup tumours, for example, generally have a favourable prognosis, and may benefit from a reduction or omission of radiotherapy or chemotherapy to spare neurological side-effects or other toxicities, as is now being prospectively tested in upcoming trials both in North America and Europe. In contrast, patients with poor prognosis Group 3 tumours may benefit from intensification of up-front therapy. Furthermore, many new targeted therapeutics are likely to be efficacious in only one subgroup, such as smoothened inhibitors for SHH pathway-driven MB [1, 2]. A phase III clinical trial randomising SMO inhibition against standard of care in relapsed SHH-MB patients will start recruiting in mid-late 2013. A method for accurate and robust classification into tumour subgroups that is applicable to standard pathology specimens is therefore of key clinical relevance.