ABSTRACT
At the time of clinical presentation, the very heterogeneous group of pediatric and adult gliomas carry a wide range of diverse somatic genomic alterations. These include chromosome-sized gains and losses, focal amplification and deletions, rearrangements resulting in transcript fusions, small insertions/deletions, and point mutations. Tumor cells pay a penalty for maintaining these abnormalities which therefore must provide cells with a competitive advantage to become engrained into the glioma genome. Here, we propose a model for gliomagenesis consisting of five consecutive phases that glioma cells have traversed prior to diagnosis. Tumor growth is repressed by activated DNA damage response pathways and dysfunctional telomeres in physiological conditions. Disruption of the p16-RB-p53 pathway and the acquisition of a telomere maintenance mechanism can bypass these bottlenecks. We relate somatic alterations to each of these steps, in order to reconstruct the life history of glioma. Understanding the story that each glioma tells at presentation may facilitate the design of novel, more effective therapeutic approaches.
Key Concepts Glioma initiating event: The first event that initiates the clonal expansion of cells
Oncogene-induced senescence: Durable growth arrest triggered by continued oncogene exposure
Replicative senescence: Durable growth arrest triggered via telomere dysfunction and activated DNA damage pathways
Crisis: Widespread cell death triggered via telomere dysfunction
Senescence bypass event: Any molecular alteration that bypasses or suppresses oncogene-induced senescence
Senescence-associated secretory phenotype (SASP): Senescent cells secrete various immunogenic cytokines, growth factors and proteases into the microenvironment
Functional redundancy: Used to describe two or more genomic changes that provide overlapping functional effect
Neutral evolution: changes due to stochastic allelic variation that do not affect fitness
Selective sweep: The elimination of genetic variation following strong positive selection effectively reducing the tumor to a single clone
Clonal event: Somatic mutation or copy number event that is conserved across all tumor cells
Subclonal event: Somatic mutation or copy number event that is only present in a subset (subclone) of tumor cells
Chromothripsis: A punctuated shattering of genomic DNA
Kataegis: Clustered regions of hypermutation
Polyploidization: The multiplication of chromosome content in a cell
Breakage fusion bridge (BFB) cycle: Cyclic fusion of uncapped telomeres, bridge formation during anaphase and subsequent breakage leading to unequal inheritance of DNA
Dicentric chromosome: Two fused chromosomes span across the mitotic spindle in anaphase, called dicentric because it has two centromeres
Double minute (DM) chromosome: Extra-chromosomal circular DNA segment lacking centromere(s) and telomeres
Immortalization event: The last straw in the immortalization process that directly leads to telomere stabilization
