High order chromatin architecture shapes the landscape of chromosomal alterations in cancer

Harvard University, Program in Biophysics, Boston, Massachusetts, USA.
Nature Biotechnology (Impact Factor: 41.51). 11/2011; 29(12):1109-13. DOI: 10.1038/nbt.2049
Source: PubMed


The accumulation of data on structural variation in cancer genomes provides an opportunity to better understand the mechanisms of genomic alterations and the forces of selection that act upon these alterations in cancer. Here we test evidence supporting the influence of two major forces, spatial chromosome structure and purifying (or negative) selection, on the landscape of somatic copy-number alterations (SCNAs) in cancer. Using a maximum likelihood approach, we compare SCNA maps and three-dimensional genome architecture as determined by genome-wide chromosome conformation capture (HiC) and described by the proposed fractal-globule model. This analysis suggests that the distribution of chromosomal alterations in cancer is spatially related to three-dimensional genomic architecture and that purifying selection, as well as positive selection, influences SCNAs during somatic evolution of cancer cells.

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    • "In both scenarios, genome reorganization precedes gene expression changes, suggesting a potential causal relationship (Apostolou et al., 2013; Phillips- Cremins et al., 2013; Wei et al., 2013; Zhang et al., 2013). Higher-order genome organization has been shown to significantly influence the distribution of genomic aberrations in both immortalized somatic cells and cancer cells, but the underlying mechanism remains elusive (De and Michor, 2011; Fudenberg et al., 2011; Koren et al., 2012; Schuster-Bö ckler and Lehner, 2012). One method of mapping genomic organization is by segmenting the genome into domains based on replication timing, which occurs in a tightly regulated cell-type-specific manner (Gilbert et al., 2010). "
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    • "During carcinogenesis, the 3D spatial arrangement of chromatin patterns experience translocation and alterations in the spatial density of chromatin at different loci of the nucleus. For example, the large-scale changes in 3D genomic architecture or the changes in spatial distribution of chromosome have been reported in cancer [6,7]. Therefore, we hypothesize that the complex genomic and epigenomic changes in carcinogenesis result in nanoscale structural alterations arising from the changes in the 3D spatial arrangement and the chromatin density variation in the cell nucleus. "
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    • "We also argue that using a confidence estimation method that accounts for the random polymer looping effect is crucial in order to characterize association of chromatin contacts with other genomic features that relate pairs of loci, such as the two ends of a somatic copy number alteration (SCNA). Two independent studies have shown enrichment of chromatin contacts between SCNA ends (De and Michor 2011; Fudenberg et al. 2011). These studies explicitly control for SCNA length and other potential biases. "
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