In mice, Ptc1 haploinsufficiency and disruption of DNA repair (DNA ligase IV inactivation) or cell cycle regulation (Kip1, Ink4d, or Ink4c inactivation), in conjunction with p53 dysfunction, predispose to medulloblastoma.
The WNT subgroup shows overexpression of genes of the WNT/wingless signalling pathway with frequent mutations of the CNNTB1 gene, loss of chromosome 6 and accumulation of nuclear β-catenin, and is most often seen in children with medulloblastomas of classical histology.This variant has a good prognosis.
1p/19q codeletion in grade 2 and 3 gliomas, nuclear beta-catenin expression in medulloblastoma) or response to the treatment (e.g. the methyl guanyl methyl transferase promoter methylation status).
<i>WNT</i>-activated nuclear β-catenin accumulating medulloblastomas were smaller than the other entities (95% CI, 5.2-22.3 cm<sup>3</sup> versus 35.1-47.6 cm<sup>3</sup>; <i>P</i> = .03).
To understand the functional role of the WNT pathway in medulloblastoma, we have investigated the intracellular distribution of beta-catenin in a series of 17 human medulloblastomas to correlate such expression with neuronal differentiation and in cultured cell models following functional silencing of the APC gene by small-interference RNA (siRNA).
Hh signaling is upregulated in basal cell carcinoma and medulloblastoma and Hh pathway inhibitors targeting the Smoothened (SMO) protein are in clinical use.
MYCN is a transcription factor that is expressed during the development of the neural crest and its dysregulation plays a major role in the pathogenesis of pediatric cancers such as neuroblastoma, medulloblastoma and rhabdomyosarcoma.
Amplification of the MYCN is the predominant marker for aggressive NB and correlates with poor prognosis, while c-MYC overexpression is a defining feature of MB subgroups inflected with aggressive biological behavior and increased likelihood of metastasis.
This finding also confirms the importance of impairment of the MYC/MAX/MXD1 axis in the development of aggressive neural tumors, because MYCN overexpression is an established genetic hallmark of malign neuroblastoma, and it is likely that MXI1 plays a relevant role in the development of medulloblastoma and glioblastoma.
We found that Sna1 directly induced transcription of N-Myc in human medulloblastoma cells and that depletion of N-Myc ablated the Sna1-induced proliferation and transformation.
The signal transducers and activators of transcription-3 (STAT3) pathway are selectively activated in CD133<sup>+</sup> MBSCs and promote tumorigenesis through regulation of c-MYC, a key genetic driver of Group 3 MB.
The impact of RNA interference (RNAi)-mediated silencing of PI3K isoforms p110α and p110δ on global gene expression was investigated by DNA microarray analysis in medulloblastoma cell lines.
Finally, the positive correlation of MYC and JAG2 also with aggressive anaplastic tumors and highly metastatic MB stages suggested that high JAG2 expression may be useful as additional marker to identify aggressive MBs.
Critically, G207 delivered to the cerebellum was able to target/treat the highly aggressive MYC-overexpressed group 3 murine medulloblastoma increasing survival vs controls.