Evolution of a cooperative genetic landscape during brain tumorigenesis Free

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Brain tumorigenesis is a complex process involving the accumulation of multiple supposedly independent genetic alterations leading to deregulation of signaling networks central to the control of cell growth and cell fate. Genome instability lends a dynamic and fluctuant character to the genetic landscape of human tumors by means of providing a route to aneuploidy. Previous work yet suggests the prevalence of nonrandom patterns of co-occurrence of distinct chromosomal imbalances in human gliomas. The classic theories regarding glioma origin and gliomagenesis are currently being reappraised. Morphologic appearance does neither necessarily reflect the origin nor the behavior of human gliomas. Since gliomas may indeed share a common (stem) cellular origin and phenotypic differences may emerge later during glioma promotion, we reasoned that we could reduce the complex nature of these tumors to the nature of sums of simpler or more fundamental things than end-stage morphology. Consistent with the idea that somatic glioma evolution selects cells and genetic events driven by self-interest, here we show that the coincidence of distinct genetic aberrations facilitates coordinated patterns of pathway deregulation that promotes gliomagenesis in a cooperative fashion. We have applied a stringent model for interfacing genome-wide gene dosage and gene expression maps in the glioma genome. Linkage of this model to the interactome of orthologous mammalian genes via a reverse network engineering algorithm identifies compelling target genes that are functionally interrelated but reside in autonomous territories of coincident chromosomal aberration. These findings lend support to the notion that a distinct genetic landscape of aneuploidy may be nonrandomly selected during glioma evolution to enable cooperative effects of multiple target genes in a global composite network of glioma promotion.