Transcriptional Characterization of Glioma Neural Stem Cells Diva ...

1.4 Pathways Involved in Glioblastoma Introduction
Rb Pathway
The importance of the inactivation of the Rb pathway in glioma progression is
evidenced by the near-universal and mutually exclusive alteration of Rb path-
way effectors and inhibitors in both primary and secondary glioblastoma [154].
RB1 is located on the long arm of chromosome 13 and similarly to the p53
pathway, the Rb pathway is also affected by homozygous deletions of the
CDKN2A locus. The CDKN2A gene is, with the exception of its alternate
reading frame isoform CDKN2A:ARF, a negative regulator of p53 signaling
as well as a regulator of the G1 checkpoint in the Rb-mediated progression of
cell cycle [154,398]. The RB1 gene is mutated in roughly 25% of high-grade
astrocytomas and the loss of the long arm of chromosome 13 characterises
the transition from low to intermediate grade gliomas. Amplification of the
CDK4 gene accounts for the functional inactivation of RB1 in roughly 15% of
high-grade gliomas, and CDK6 is also amplified but at a lower frequency [154].
Deregulation of Rb signaling leading to G1/S progression appears to be a crit-
ical event in gliomagenesis whether or not inactivation of RB1 is an initiating
event [100]. Cell cycle progression is regulated by the activities of complexes of
cyclins and CDKs, which phosphorylate RB1 and block its growth-inhibitory
functions [318]. G1 progression is controlled by the D-type cyclins, which
form active complexes with CDK4 or CDK6, and E-type cyclins in associa-
tion with CDK2 (Fig 1.4) [398]. Within the TCGA dataset, 77% of samples
showed genetic alterations in the Rb pathway. Among these, the deletion of the
CDKN2A/CDKN2B locus on the short arm of chromosome nine was the most
common event, followed by amplification of the CDK4 locus [326]. CDKN2B
and CDKN2A lie adjacent in the short arm of chromosome nine and together
define a region that is frequently mutated and deleted in a wide variety of
tumours [233]. CDKN2A and CDKN2B both form complexes with CDK4,
CDK6 and cyclin D to block their activation and progression of cell cycle into
the G1/S phase [382,454]. Interestingly, all samples with RB1 nucleotide sub-
stitutions lacked CDKN2A/CDKN2B locus deletion, suggesting that this type
of RB1 inactivation obviates the genetic pressure for activation of upstream
cyclin and cyclin-dependent kinase complexes. Thus, it would be reasonable
to speculate that patients with deletions in CDKN2A or CDKN2B or with
amplifications in CDK4 or CDK6 could benefit from a treatment with CDK
inhibitors, unlikely to affect patients with RB1 mutation [326]. However, nu-
merous in vitro and in vivo assays have demonstrated that the neutralisation
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