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

Abstract

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 cancer1. 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 model2,3. 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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Figure 1: 3D proximity as mechanism for SCNA formation.
Figure 2: Heatmaps for chromosome 17 at 1 Mb resolution.
Figure 3: Selecting a model of SCNA formation based on its consistency with the 24,310 observed SCNAs that do not span highly recurrent SCNA regions listed in reference 1.
Figure 4: Permutation analysis of the relationship between SCNAs and megabase-level structure of HiC chromosomal interactions.

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Acknowledgements

We thank members of the Mirny Lab for helpful conversations, in particular with C. McFarland regarding purifying selection and M. Imakaev regarding fractal globules. We thank C. Mermel for an introduction to SCNA data. We thank V. Agarwala, J. Engrietz, R. McCord and J. Dekker for helpful comments and suggestions. This work was supported by the US National Institutes of Health/National Cancer Institute Physical Sciences Oncology Center at MIT (U54CA143874). G.G. and M.M. are TCGA-funded investigators (NIH U24CA143845, U24CA144025 and U24CA143867).

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G.F. designed the study, performed data analysis and wrote the paper; G.G. and M.M. provided expertise in SCNA analysis and developed the manuscript; L.A.M. designed the study, performed initial data analysis and wrote the paper.

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Correspondence to Leonid A Mirny.

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The authors declare no competing financial interests.

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Supplementary Figures 1–9 and Supplementary Table 1 (PDF 1161 kb)

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Fudenberg, G., Getz, G., Meyerson, M. et al. High order chromatin architecture shapes the landscape of chromosomal alterations in cancer. Nat Biotechnol 29, 1109–1113 (2011). https://doi.org/10.1038/nbt.2049

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