Reconstructing the Molecular Life History of Gliomas

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.\n\nKey ConceptsGlioma initiating event: The first event that initiates the clonal expansion of cells\n\nOncogene-induced senescence: Durable growth arrest triggered by continued oncogene exposure\n\nReplicative senescence: Durable growth arrest triggered via telomere dysfunction and activated DNA damage pathways\n\nCrisis: Widespread cell death triggered via telomere dysfunction\n\nSenescence bypass event: Any molecular alteration that bypasses or suppresses oncogene-induced senescence\n\nSenescence-associated secretory phenotype (SASP): Senescent cells secrete various immunogenic cytokines, growth factors and proteases into the microenvironment\n\nFunctional redundancy: Used to describe two or more genomic changes that provide overlapping functional effect\n\nNeutral evolution: changes due to stochastic allelic variation that do not affect fitness\n\nSelective sweep: The elimination of genetic variation following strong positive selection effectively reducing the tumor to a single clone\n\nClonal event: Somatic mutation or copy number event that is conserved across all tumor cells\n\nSubclonal event: Somatic mutation or copy number event that is only present in a subset (subclone) of tumor cells\n\nChromothripsis: A punctuated shattering of genomic DNA\n\nKataegis: Clustered regions of hypermutation\n\nPolyploidization: The multiplication of chromosome content in a cell\n\nBreakage fusion bridge (BFB) cycle: Cyclic fusion of uncapped telomeres, bridge formation during anaphase and subsequent breakage leading to unequal inheritance of DNA\n\nDicentric chromosome: Two fused chromosomes span across the mitotic spindle in anaphase, called dicentric because it has two centromeres\n\nDouble minute (DM) chromosome: Extra-chromosomal circular DNA segment lacking centromere(s) and telomeres\n\nImmortalization event: The last straw in the immortalization process that directly leads to telomere stabilization