Loss of 17p13.3 (38% of medulloblastomas) was found across all of the histopathological variants, whereas MYCC/MYCN amplification (6%/8% of medulloblastomas) was significantly associated with the large cell/anaplastic phenotype.
Integrated analysis of miRNA and miRNA targets regulated by both PDGFRβ and c-MYC reveals that increased expression of JAG2, a target of miR-1280, is associated with high metastatic dissemination at diagnosis and a poor outcome in MB patients.
MK-8628 showed therapeutic efficacy against in vitro and in vivo models of MYC-amplified medulloblastoma by inducing apoptotic cell death and cell cycle arrest.
GLI1 transcript was expressed in medulloblastomas with ATOH1 transcript, whereas high levels of MYC transcript were unrelated to NEUROG1 or ATOH1 expression.
The association of clinically aggressive medulloblastoma with MYC expression, large cell/anaplastic change and high levels of photoreceptor differentiation transcripts has also been noted in several studies.
There is a strong association between anaplastic/large-cell tumours and MYC amplification, which has previously been linked with aggressive disease, but associations between abnormalities on chromosome 17 and anaplastic/large-cell MBs and between abnormalities in the shh/PTCH pathway and the desmoplastic variant are more controversial.
We find that higher MYC levels are associated with increased EZH2, and pharmacological blockade of EZH2 is a potential therapeutic strategy for aggressive medulloblastoma with elevated MYC.
This study highlights B7-H3 as a viable target in MB angiogenesis, and that the expression of miR-29 can inhibit B7-H3 and sensitize MB cells to treatment with MYC-inhibiting drugs.
In cell lines, SHH MB, which are low-MYC expressing, demonstrated both constitutive and inducible expression of PD-L1 while those in Group 3/4 that expressed high levels of MYC had only inducible expression.
Our findings identify P53-MYC interactions at medulloblastoma relapse as biomarkers of clinically aggressive disease that may be targeted therapeutically.
Profiling six FISH biomarkers (GLI2, MYC, chromosome 11 [chr11], chr14, 17p, and 17q) on formalin-fixed paraffin-embedded tissues, we can reliably and reproducibly identify very low-risk and very high-risk patients within SHH, Group 3, and Group 4 medulloblastomas.
These observations demonstrate that the c-myc gene is often amplified and/or rearranged in human medulloblastomas and suggest that amplification of this gene provides a growth advantage for medulloblastoma cells in vitro and in vivo.
For pediatric CNS neoplasms, only medulloblastoma has been investigated in adequate numbers; a small percentage exhibit amplification of either the N-myc or c-myc genes.
Our results indicate a low incidence of N-myc and c-myc gene amplification in medulloblastomas, suggesting that the oncogenic mechanism in these neoplasms is not closely related to DNA gene amplification.