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

Nature Biotechnology volume 29, pages 11091113 (2011) | Download Citation


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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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).

Author information


  1. Harvard University, Program in Biophysics, Boston, Massachusetts, USA.

    • Geoff Fudenberg
  2. The Broad Institute of the Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA.

    • Gad Getz
    • , Matthew Meyerson
    •  & Leonid A Mirny
  3. Harvard Medical School, Boston, Massachusetts, USA.

    • Matthew Meyerson
  4. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Matthew Meyerson
  5. Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Matthew Meyerson
  6. Harvard-MIT, Division of Health Sciences and Technology, Cambridge, Massachusetts, USA.

    • Leonid A Mirny
  7. Department of Physics, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Leonid A Mirny


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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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Leonid A Mirny.

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