DNA secondary structures and epigenetic determinants of cancer genome evolution

Abstract

An unstable genome is a hallmark of many cancers. It is unclear, however, whether some mutagenic features driving somatic alterations in cancer are encoded in the genome sequence and whether they can operate in a tissue-specific manner. We performed a genome-wide analysis of 663,446 DNA breakpoints associated with somatic copy-number alterations (SCNAs) from 2,792 cancer samples classified into 26 cancer types. Many SCNA breakpoints are spatially clustered in cancer genomes. We observed a significant enrichment for G-quadruplex sequences (G4s) in the vicinity of SCNA breakpoints and established that SCNAs show a strand bias consistent with G4-mediated structural alterations. Notably, abnormal hypomethylation near G4s-rich regions is a common signature for many SCNA breakpoint hotspots. We propose a mechanistic hypothesis that abnormal hypomethylation in genomic regions enriched for G4s acts as a mutagenic factor driving tissue-specific mutational landscapes in cancer.

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Figure 1: Spatial distribution of breakpoint hotspots in cancer genomes and genomes of healthy human subjects.
Figure 2: Association between G-quadruplex–forming sequences and breakpoint hotspots.
Figure 3: Role of G-quadruplex structures in the generation of breakpoint hotspots.
Figure 4: A mechanistic hypothesis of epigenetic involvement in the generation of breakpoints in cancer genomes.

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Acknowledgements

We would like to thank G. Parmigiani, J. Widom, N. Maizels, G.-Ch. Yuan, R. Beroukhim and D. Patel for discussions and comments. 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 US National Cancer Institute's initiative to found Physical Science–Oncology Centers (U54CA143798).

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S.D. and F.M. designed the research and wrote the manuscript. S.D. performed the research.

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Correspondence to Franziska Michor.

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The authors declare no competing financial interests.

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Supplementary Figures 1–3, Supplementary Tables 1–9 and Supplementary Methods (PDF 508 kb)

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De, S., Michor, F. DNA secondary structures and epigenetic determinants of cancer genome evolution. Nat Struct Mol Biol 18, 950–955 (2011). https://doi.org/10.1038/nsmb.2089

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