Glioblastoma multiforme (GBM) is one of the most devastating human cancers, notorious for its fast growing nature, infiltrative growth, resistance to radiotherapy, and rapid progression from diagnosis to death (1
). Homozygous deletion of the p16INK4a
locus on chromosome 9p21.3 is a signature genetic event that drives the pathogenesis of GBM (2
). Deletion of this locus is thought to be strongly selected for during the pathogenesis of GBM and other tumor types because it simultaneously inactivates three tumor suppressor genes: the p16INK4a
cyclin-dependent kinase (cdk) inhibitors and p14ARF
, which modulates the activity of the p53 tumor suppressor (4
p16INK4a is the prototype member of the INK4 family of cdk inhibitors, which includes p16INK4a, p15INK4b, p18INK4c, and p19INK4d. These four proteins have ~30% amino acid sequence similarity and share potent cyclin-dependent kinase (cdk) inhibitory activity, but are thought to differ from each other in their patterns of expression and their relative affinities for different cdks. Of the four genes, p16INK4a plays the most prominent role as a tumor suppressor gene in human cancer, as it is deleted or mutated in the majority of common human tumor types and the cause of an inherited cancer predisposition syndrome. In contrast, p15INK4b and p18INK4c are thought to play more limited roles as human tumor suppressors, and p19INK4d is thought not to be involved in cancer pathogenesis.
Two recent studies have shown that deletions and mutations of p18INK4c
, together with deletions and mutations of the p16INK4a
genes, drive the pathogenesis of human GBM (6
). When taken together with other prior studies identifying deletions and mutations of p18INK4c
in several other tumor types and showing that p18INK4c
-deficient mice are tumor prone, these recent studies have suggested that inactivation of p18INK4c
may play a perhaps underappreciated role in human cancer pathogenesis. As such, this review will provide a brief history of the discovery of p18INK4c
, summarize the studies that link it to cancers in mice and humans, and provide a forward-looking assessment of the role of p18INK4c
inactivation in the pathogenesis of GBM ().
Depiction of sequential INK4 inactivation during GBM progression resulting in a tumor with homogeneous loss of p16INK4a and heterogeneous loss of p18INK4c.