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DNA replication timing and long-range DNA interactions predict mutational landscapes of cancer genomes

Nature Biotechnology volume 29, pages 1103–1108 (2011)Cite this article

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Abstract

Somatic copy-number alterations (SCNA) are a hallmark of many cancer types, but the mechanistic basis underlying their genome-wide patterns remains incompletely understood. Here we integrate data on DNA replication timing, long-range interactions between genomic material, and 331,724 SCNAs from 2,792 cancer samples classified into 26 cancer types. We report that genomic regions of similar replication timing are clustered spatially in the nucleus, that the two boundaries of SCNAs tend to be found in such regions, and that regions replicated early and late display distinct patterns of frequencies of SCNA boundaries, SCNA size and a preference for deletions over insertions. We show that long-range interaction and replication timing data alone can identify a significant proportion of SCNAs in an independent test data set. We propose a model for the generation of SCNAs in cancer, suggesting that data on spatial proximity of regions replicating at the same time can be used to predict the mutational landscapes of cancer genomes.

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Figure 1: Long-range DNA interactions and the distribution of SNCAs with regard to replication timing zones.
Figure 2: SCNA frequencies vary between different replication timing zones.
Figure 3: Genome-wide distributions of long-range interactions and SCNAs.

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Acknowledgements

We would like to thank K. Polyak, A. Melnick, K.J. Patel, A. Chakravarti and R. Beroukhim for comments and discussions. S.D. is a recipient of Human Frontier Science Program long-term fellowship and is a Research Fellow at King's College, Cambridge. This work was funded by the National Cancer Institute's initiative to found Physical Science-Oncology Centers (U54CA143798).

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Authors and Affiliations

  1. Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

    Subhajyoti De & Franziska Michor

  2. Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA

    Subhajyoti De & Franziska Michor

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  1. Subhajyoti De
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  2. Franziska Michor
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Contributions

S.D. and F.M. designed the experiments and wrote the paper. S.D. performed the analysis.

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Correspondence to Subhajyoti De or Franziska Michor.

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The authors declare no competing financial interests.

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De, S., Michor, F. DNA replication timing and long-range DNA interactions predict mutational landscapes of cancer genomes. Nat Biotechnol 29, 1103–1108 (2011). https://doi.org/10.1038/nbt.2030

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