468 DKK1 SFRP1 GLI1 GAB1 FILA YAP1 NPR3 KCNA1 Acta Neuropathol (2012) 123:465–472 Table 1 Antibodies used for immunohistochemical assignment of medulloblastoma subgroup afﬁliation Antigens Subgroup(s) Antibody sources Company (catalog#) Dilution(s) Reference(s) CTNNB1 (nuclear) WNT Mouse monoclonal BD Transduction Laboratories (ab610154) [8, 11–13, 28, 37] WNT SHH SHH SHH WNT/SHH WNT/SHH Group C Group C Group D Mouse monoclonal Mouse monoclonal Rabbit polyclonal Rabbit polyclonal Goat polyclonal Rabbit polyclonal Mouse monoclonal Mouse monoclonal Rabbit polyclonal Rabbit polyclonal Rabbit polyclonal Ventana (760-4242) Cell Signaling Technologies Abnova (H00022943-M11) Abcam (ab4193) Millipore (ab3444) Santa Cruz Biotechnology (sc-6152) Abcam (ab27439) Fitzgerald (10R-F113A) Santa Cruz (sc-101199) Abcam (ab37617) Sigma (HPA031065) Abcam (ab32433) 1:100 1:800 1:500 1:100 1:2,000 1:5,000 1:50 1:100 1:50 1:200 1:30 1:2,000 [2, 14] [15, 39] [28, 37] [28, 37, 38] [28] [2] [11] [11] [11] [28, 37, 38] [28, 37, 38] immunohistochemical staining for b-catenin, and mono- somy six (deletion of one copy of chromosome 6 in the tumor). Which, if any of these markers is a gold standard for the diagnosis of Wnt medulloblastoma is unclear, as medulloblastomas with a clear Wnt transcriptional signature that do not have monosomy six have been reported [28]. The recent report of a single medulloblastoma with mutations in both CTNNB1 and PTCH also complicates the story [32]. Indeed, over-representation of genes in the Wnt pathway has also been reported in Shh and Group 3 medulloblastomas, although this ﬁnding is of unknown signiﬁcance [28]. Medulloblastomas with large cell/anaplastic histology have also been reported in the Wnt subgroup, although they appear to maintain the excellent prognosis associated with the Wnt subgroup [12]. Which of monosomy 6, nuclear staining for b-catenin, mutation of CTNNB1, immunohistochemical staining for DKK1 [28, 48], or a transcriptional signature that clusters with other ‘Wnt’ tumors should be used as a gold standard for the diagnosis of Wnt medulloblastoma awaits further validation on larger cohorts of well-characterized medulloblastomas. Overall medulloblastoma is more common in males, however, the gender ratio for Wnt medulloblastomas is about 1:1 male:female. Wnt medulloblastomas can occur at all ages, but are uncommon in infants. Other than monosomy six, there are few other regions of genetic ampliﬁcation or deletion in the genome of Wnt medulloblastomas [28]. Recently a mouse model of Wnt medulloblastoma was published, which suggested that Wnt medulloblastomas arise from the lower rhombic lip of the cerebellum [17]. This mouse will undoubtedly serve as a valuable tool in the pre- clinical assessment of novel therapeutics. As most patients with Wnt medulloblastoma survive, it is possible that they are being over treated with current therapies which are quite 123 morbid, and there is an active discussion of a clinical trial of therapy de-escalation in this patient population. Sonic hedgehog subgroup The Shh group of medulloblastomas are named after the Sonic Hedgehog signaling pathway, which is thought to drive tumor initiation in many, if not all such cases. Indi- viduals with germline mutations in the Shh receptor PTCH have Gorlin syndrome, which includes a predisposition to medulloblastoma [3, 47]. Similarly, individuals with germ- line mutations of the Shh inhibitor SUFU are predisposed to medulloblastoma, particularly infantile medulloblastoma [5, 33, 42, 46]. Similarly, somatic mutations of PTCH, SMO, and SUFU, as well as ampliﬁcations of GLI1 and GLI2 have been found in sporadic medulloblastoma [27, 30, 46]. These genetic data implicating Shh signaling in the etiology of this group of tumors has lead to the current proposal to formally name them ‘Sonic Hedgehog’ subgroup medulloblastomas. Sonic hedgehog subgroup medulloblastomas have largely been identiﬁed on the basis of transcriptional proﬁling [7, 22, 28, 29, 41, 48]. Others approaches to identify Shh medullo- blastomas have included immunohistochemical staining for SFRP1 [2, 28, 48], or GAB1 [11]. Deletion of chromosome 9q appears to be limited to Shh medulloblastomas, which is appropriate as the PTCH gene is located at chromosome 9q22 [28]. The vast majority of published mouse models of medulloblastoma belong to the Shh subgroup of tumors [20]. The temporal incidence of human Shh medulloblastoma is curiously dichotomous, in that it is very frequent in both infants (0–3 years) and adults ([16 years), but much less frequent in children (3–16 years). The extent to which adult