466 medulloblastoma (Wnt, Shh, Group 3, and Group 4). Par- ticipants outlined the demographic, transcriptional, genetic, and clinical differences between the four subgroups. While it is anticipated that the molecular classiﬁcation of medul- loblastoma will continue to evolve and diversify in the future as larger cohorts are studied at greater depth, herein we outline the current consensus nomenclature, and the differences between the medulloblastoma subgroups. Keywords SHH WNT Medulloblastoma Consensus Subgroups Group 3 Group 4 Introduction Current classiﬁcation schemes for medulloblastoma are based primarily on morphology (histopathology), and include variants such as desmoplastic/nodular, MBEN (medulloblastoma with extensive nodularity), classic medulloblastoma, large cell, and anaplastic medulloblas- toma. With recent developments in the ability to monitor transcription across the genome in the setting of a single experiment, various groups have started to sub-classify medulloblastoma on the basis of differences in the tran- scriptome [36]. Several laboratories across the globe have published on this topic in the recent past, with largely convergent conclusions [2, 7, 14, 22, 28, 30, 48]. This transcriptional approach to tumor sub-classiﬁcation has also been applied to a number of different non-medullo- blastoma histologies [4, 16, 18, 31, 35, 43], with the underlying assumption that tumors with similar tran- scriptomes will behave in a biologically similar manner, allowing a transcriptionally driven classiﬁcation to serve as a guide for successful anti-neoplastic therapy. The number of ‘subgroups’ of medulloblastoma identiﬁed among cohorts of medulloblastoma is largely dependant on the number of individual tumors within a given cohort, with larger cohorts identifying additional levels of hierarchical complexity [7, 22, 28, 36]. On the basis of the published literature, and some unpublished data presented at a recent consensus conference in Boston, Massachusetts, members from many of the laboratories publishing on this topic agreed that there were four principal transcriptional subgroups of medulloblastoma, with many of these subgroups showing a subsequent level of hierarchical structure that will be des- ignated the subtypes of the subgroups (Fig. 1). The true number of subtypes for each of the subgroups is currently unknown, but it is likely more than one subtype for each subgroup. The four principal subgroups of medulloblastoma were named as follows: Wnt, Shh, Group 3, and Group 4 (Fig. 2). The Wnt and Shh (Sonic Hedgehog) were named for the signaling pathways thought to play prominent roles in the pathogenesis of that subgroup. Since less is known about the 123 Acta Neuropathol (2012) 123:465–472 biology of the remaining two subgroups, the consensus was to retain generic names for the present until the underlying biology driving these subgroups was better delineated. There is evidence for the existence of subtypes within the sub- groups, particularly for Group 3, which is also reﬂected by the fact that among Non-WNT, Non-SHH tumors, there may be a small fraction of ‘‘intermediate’’ tumors that would be assigned to Group 3 or Group 4 based on the clustering algorithm applied [7]. While the subsets of the subgroups seem readily apparent, they are not well characterized at this point and as such the consensus was to name them using Greek letters (a, b, c, etc.) until additional characterization was available from multiple centers, on much larger cohorts (Fig. 1). Since the four groups as proposed are clearly dis- tinct in terms of demographics, histology, DNA copy- number aberrations, and clinical outcome as also nicely summarized in a meta-analysis paper in the same issue of this journal [21], the authors consider it highly useful to start using these subgroups in the clinic. More speciﬁcally, molecular subgrouping will not only contribute to identify target cohorts for certain drugs (e.g., SHH inhibitors), but also add signiﬁcantly to outcome prediction by the time of diagnosis [21], much more than any of the established clin- ical markers such as patient age, metastatic stage at diagnosis, level of resection, and histological subtype according to the WHO classiﬁcation [25]. To this end, Table 1 summarizes markers that have been proposed to perform subgrouping by immunostaining from various groups. Although it is evident that few tumors will either be positive for more than one marker or negative for all markers [28], it is encouraging that using two markers that are sup- posed to select the same subgroup (such as SFRP1 and GAB1 for SHH tumors) resulted in a very high overlap in a study published in the same issue of this journal [23]. In the fol- lowing, the distinctive characteristics of these four core subgroups are described in more detail. Wnt subgroup The best known of the medulloblastoma subgroups is the Wnt subgroup due to its very good long-term prognosis in comparison to other subgroups [8, 11, 13, 15, 22, 28, 39, 48]. Indeed, long-term survival rates for patients with Wnt medulloblastoma likely exceed 90%, with those patients who die succumbing more often to complications of ther- apy or secondary neoplasms rather than to recurrent Wnt medulloblastoma [12]. Germline mutations of the Wnt pathway inhibitor APC predispose to Turcot syndrome, which includes a proclivity to medulloblastoma, in addi- tion, somatic mutations of CTNNB1 encoding b-catenin have been found in sporadic medulloblastomas [19, 50]. These strong germline and somatic genetic data strongly