====== Medulloblastoma molecular biology ======
Advances in [[molecular]] profiling have uncovered significant heterogeneity among [[medulloblastoma]]s and led to the identification of four distinct subgroups (wingless [[[Medulloblastoma, WNT-activated]]], [[sonic hedgehog medulloblastoma]] [SHH], [[group 3 medulloblastoma]], and [[group 4 medulloblastoma]]) that represent distinct disease entities in both underlying biology and clinical characteristics. The rapidly expanding repertoire of tools to study developmental and cancer biology is providing a wealth of knowledge about these [[embryonal tumor]]s and is continuously refining the understanding of this complex [[cancer]]. In a review of Juraschka and Taylor, the history of discovery in medulloblastoma is discussed, setting a foundation to outline the current state of understanding of the molecular underpinnings of this disease, with a focus on [[genomic]] events that define the aforementioned subgroups and evolving areas of focus, such as the cell of origin of medulloblastoma and medulloblastoma subtypes. With these recent discoveries in mind, the current state of medulloblastoma treatment and clinical trials are reviewed, including a novel risk stratification system that accounts for the molecular [[biomarker]]s of patients with a high risk for refractory disease. Lastly, critical areas of focus for future basic science and clinical research on this disease are discussed, such as the complexities of medulloblastoma metastases and recurrence as well as the priorities and strategies to implement in future clinical trials
((Juraschka K, Taylor MD. Medulloblastoma in the age of molecular subgroups: a
review. J Neurosurg Pediatr. 2019 Oct 1;24(4):353-363. doi:
10.3171/2019.5.PEDS18381. Review. PubMed PMID: 31574483.
)).
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Pomeroy et al., demonstrated that [[medulloblastoma]]s are molecularly distinct from other brain tumours including [[primitive neuroectodermal tumor]]s (PNETs), atypical teratoid/rhabdoid tumours (AT/RTs) and malignant gliomas. Previously unrecognized evidence supporting the derivation of medulloblastomas from cerebellar granule cells through activation of the Sonic Hedgehog (SHH) pathway was also revealed. 

They showed further that the clinical outcome of children with medulloblastomas is highly predictable on the basis of the gene expression profiles of their tumours at diagnosis
((Pomeroy SL, Tamayo P, Gaasenbeek M, Sturla LM, Angelo M, McLaughlin ME, Kim
JY, Goumnerova LC, Black PM, Lau C, Allen JC, Zagzag D, Olson JM, Curran T,
Wetmore C, Biegel JA, Poggio T, Mukherjee S, Rifkin R, Califano A, Stolovitzky G,
Louis DN, Mesirov JP, Lander ES, Golub TR. Prediction of central nervous system
embryonal tumour outcome based on gene expression. Nature. 2002 Jan
24;415(6870):436-42. PubMed PMID: 11807556.)).

The molecular genetic alterations in medulloblastoma can be divided into 3 groups:

1.- Non-random chromosomal abnormalities (e.g. consistent deletion of 17p markers) has been shown in 35-40 %.


2.- Information from gene profiling:

[[ZIC]] and [[NSCL1]] were the genes most closely correlated with medulloblastoma.

Certain genes were associated with more favorable outcome (using 8 genes a pattern associated with 80% 5-year survival compared to 17% when the pattern was lacking)
((Pomeroy SL, Tamayo P, Gaasenbeek M, Sturla LM, Angelo M, McLaughlin ME, Kim JY, Goumnerova LC, Black PM, Lau C, Allen JC, Zagzag D, Olson JM, Cur- ran T, Wetmore C, Biegel JA, Poggio T, Mukherjee S, Rifkin R, Califano A, Stolovitzky G, Louis DN, Mesir- ov JP, Lander ES, Golub TR. Prediction of central nervous system embryonal tumour outcome based on gene expression. Nature. 2002; 415:436–442)).

3.- abnormalities in signal transduction pathways: e.g. neurotrophin signaling pathway (important in cerebellar development) or Sonic hedgehog (Shh)
((Corcoran RB, Scott MP. Oxysterols stimulate Sonic hedgehog signal transduction and proliferation of medulloblastoma cells. Proc Natl Acad Sci U S A. 2006; 103:8408–8413)).
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[[Sterol]] synthesis is required for [[Sonic hedgehog signaling pathway]]. 

Errors in Shh signal transduction play important roles in the formation of human tumors, including medulloblastoma (MB). It is not clear which products of sterol synthesis are necessary for Shh signal transduction or how they act. Here we show that cholesterol or specific oxysterols are the critical products of sterol synthesis required for Shh pathway signal transduction in MB cells. In MB cells, sterol synthesis inhibitors reduce Shh target gene transcription and block Shh pathway-dependent proliferation. These effects of sterol synthesis inhibitors can be reversed by exogenous cholesterol or specific oxysterols. We also show that certain oxysterols can maximally activate Shh target gene transcription through the Smoothened (Smo) protein as effectively as the known Smo full agonist, SAG. Thus, sterols are required and sufficient for Shh pathway activation. These results suggest that oxysterols may be critical regulators of Smo, and thereby Shh signal transduction. Inhibition of Shh signaling by sterol synthesis inhibitors may offer a novel approach to the treatment of MB and other Shh pathway-dependent human tumors
((Corcoran RB, Scott MP. Oxysterols stimulate Sonic hedgehog signal transduction
and proliferation of medulloblastoma cells. Proc Natl Acad Sci U S A. 2006 May
30;103(22):8408-13. Epub 2006 May 17. PubMed PMID: 16707575; PubMed Central
PMCID: PMC1462959.
)).