Gene Expression Analyses of the Spatio-Temporal Relationships of Human Medulloblastoma Subgroups during Early Human Neurogenesis

Abstract

Medulloblastoma is the most common form of malignant paediatric brain tumour and is the leading cause of childhood cancer related mortality. The four molecular subgroups of medulloblastoma that have been identified – WNT, SHH, Group 3 and Group 4 - have molecular and topographical characteristics suggestive of different cells of origin. Definitive identification of the cell(s) of origin of the medulloblastoma subgroups, particularly the poorer prognosis Group 3 and Group 4 medulloblastoma, is critical to understand the pathogenesis of the disease, and ultimately for the development of more effective treatment options. To address this issue, the gene expression profiles of normal human neural tissues and cell types representing a broad neuro-developmental continuum, were compared to those of two independent cohorts of primary human medulloblastoma specimens. Clustering, co-expression network, and gene expression analyses revealed that WNT and SHH medulloblastoma may be derived from distinct neural stem cell populations during early embryonic development, while the transcriptional profiles of Group 3 and Group 4 medulloblastoma resemble cerebellar granule neuron precursors at weeks 10–15 and 20–30 of embryogenesis, respectively. Our data indicate that Group 3 medulloblastoma may arise through abnormal neuronal differentiation, whereas deregulation of synaptic pruning-associated apoptosis may be driving Group 4 tumorigenesis. Overall, these data provide significant new insight into the spatio-temporal relationships and molecular pathogenesis of the human medulloblastoma subgroups, and provide an important framework for the development of more refined model systems, and ultimately improved therapeutic strategies.

Functional Genomics Identifies Tis21-Dependent Mechanisms and Putative Cancer Drug Targets Underlying Medulloblastoma Shh-Type Development

“…Evidences of a deregulated clathrin-mediated endocytosis pattern have been reported for MB group 4 during early human neurogenesis (Hooper et al, 2014), and detected in our Set B (data not shown) as well as in Set A, where a large number of deregulated genes belongs to this signaling: Rab11fip4 (Horgan and McCaffrey, 2009), Ehbp1 (Guilherme et al, 2004), Rab11fip2 (Fan et al, 2004), Zfyve20 (de Renzis et al, 2002; Naslavsky et al, 2004), Cxcl12 (Fan et al, 2004; Teicher and Fricker, 2010; Zhu et al, 2012), Sgsm2 (Yang et al, 2007), Ckap5 (Foraker et al, 2012), Vps35 (Foraker et al, 2012), and Rab18 (Foraker et al, 2012). …”

“…In fact, a large number of deregulated genes in our Set A are also involved in the delayed differentiation of retinal cell types. Notably, it has been previously shown a parallelism between MB and retinal development; in fact, the analysis of cell populations in MB-derived from GCPs (particularly the group 3) suggests the occurrence of a potential aberrant trans-lineage differentiation into retinal neuronal precursors (Kool et al, 2008; Hooper et al, 2014). Here, given the large number of genes comprised in set A that is deregulated during the retinal cell development, we want to focus our attention on the timing of exit from the cell cycle, a crucial step in retinal cell development and differentiation, which is under the influence of Shh signaling, as it occurs in the development of MB Shh-type (Dyer, 2004).…”

“…An intriguing observation concerns the fact that three genes in Set A whose expression is significantly modified - namely, Nlk, Raf1 , and Ppp2r2b —are markers for group 3 medulloblastoma (Kool et al, 2008; Gibson et al, 2010; Northcott et al, 2011, 2012c; Taylor et al, 2012; Hooper et al, 2014). Moreover, Nlk is among the genes of Set A modified in retinal development, and it has been suggested that cerebellar and retinal progenitor cells have common evolutionary origin [76].…”

“…Moreover, Nlk is among the genes of Set A modified in retinal development, and it has been suggested that cerebellar and retinal progenitor cells have common evolutionary origin [76]. It is also worth noting that, according to references (Kool et al, 2008; Hooper et al, 2014), among the markers for group 3 MB there are many genes involved in retinal development; in our Set A many genes as well are involved in this process, Nlk being common. Additionally, in Set A there are at least two genes whose expression is modified, Gli1 and Pdgfd , which are markers of Shh-type medulloblastoma (Kool et al, 2008; Gibson et al, 2010; Northcott et al, 2011, 2012c; Taylor et al, 2012; Hooper et al, 2014).…”

Differences in the prognostic value of tumor extent of resection among the molecular subgroups of medulloblastoma:A single centre study of 113 cases

“…Recent progress in the genomic characterization of medulloblastoma has shown that medulloblastoma is a heterogeneous disease comprised of 4 molecular subgroups: sonic hedgehog (SHH), wingless (WNT), Group 3, and Group 4 [4][5][6][7][8][9] . Signaling pathways or biological programs driving the pathogenesis of Group 3 and Group 4 subgroups have remained largely elusive [10] .…”