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Complex landscapes of somatic rearrangement in human breast cancer genomes

Abstract

Multiple somatic rearrangements are often found in cancer genomes; however, the underlying processes of rearrangement and their contribution to cancer development are poorly characterized. Here we use a paired-end sequencing strategy to identify somatic rearrangements in breast cancer genomes. There are more rearrangements in some breast cancers than previously appreciated. Rearrangements are more frequent over gene footprints and most are intrachromosomal. Multiple rearrangement architectures are present, but tandem duplications are particularly common in some cancers, perhaps reflecting a specific defect in DNA maintenance. Short overlapping sequences at most rearrangement junctions indicate that these have been mediated by non-homologous end-joining DNA repair, although varying sequence patterns indicate that multiple processes of this type are operative. Several expressed in-frame fusion genes were identified but none was recurrent. The study provides a new perspective on cancer genomes, highlighting the diversity of somatic rearrangements and their potential contribution to cancer development.

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Figure 1: Somatic rearrangements observed in six of the twenty-four breast cancer samples screened.
Figure 2: Extent of overlapping microhomology at different architectural classes of rearrangement junctions.
Figure 3: ETV6–ITPR2 , an expressed, in-frame fusion gene generated by a 15-Mb inversion in the primary breast cancer PD3668a.

References

  1. Kaye, F. J. Mutation-associated fusion cancer genes in solid tumors. Mol. Cancer Ther. 8, 1399–1408 (2009)

    Article  CAS  Google Scholar 

  2. Mitelman, F., Johansson, B. & Mertens, F. Fusion genes and rearranged genes as a linear function of chromosome aberrations in cancer. Nature Genet. 36, 331–334 (2004)

    Article  CAS  Google Scholar 

  3. Mitelman, F., Johansson, B. & Mertens, F. The impact of translocations and gene fusions on cancer causation. Nature Rev. Cancer 7, 233–245 (2007)

    Article  CAS  Google Scholar 

  4. Futreal, P. A. et al. A census of human cancer genes. Nature Rev. Cancer 4, 177–183 (2004)

    Article  CAS  Google Scholar 

  5. Stratton, M. R., Campbell, P. J. & Futreal, P. A. The cancer genome. Nature 458, 719–724 (2009)

    Article  CAS  ADS  Google Scholar 

  6. Sawyers, C. L. Chronic myeloid leukemia. N. Engl. J. Med. 340, 1330–1340 (1999)

    Article  CAS  Google Scholar 

  7. Tomlins, S. A. et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 310, 644–648 (2005)

    Article  CAS  ADS  Google Scholar 

  8. Soda, M. et al. Identification of the transforming EML4ALK fusion gene in non-small-cell lung cancer. Nature 448, 561–566 (2007)

    Article  CAS  ADS  Google Scholar 

  9. Höglund, M., Gisselsson, D., Sall, T. & Mitelman, F. Coping with complexity. multivariate analysis of tumor karyotypes. Cancer Genet. Cytogenet. 135, 103–109 (2002)

    Article  Google Scholar 

  10. Bignell, G. R. et al. Architectures of somatic genomic rearrangement in human cancer amplicons at sequence-level resolution. Genome Res. 17, 1296–1303 (2007)

    Article  CAS  Google Scholar 

  11. Volik, S. et al. End-sequence profiling: sequence-based analysis of aberrant genomes. Proc. Natl Acad. Sci. USA 100, 7696–7701 (2003)

    Article  ADS  Google Scholar 

  12. Ruan, Y. et al. Fusion transcripts and transcribed retrotransposed loci discovered through comprehensive transcriptome analysis using Paired-End diTags (PETs). Genome Res. 17, 828–838 (2007)

    Article  CAS  Google Scholar 

  13. Greenman, C. et al. Patterns of somatic mutation in human cancer genomes. Nature 446, 153–158 (2007)

    Article  CAS  ADS  Google Scholar 

  14. Wood, L. D. et al. The genomic landscapes of human breast and colorectal cancers. Science 318, 1108–1113 (2007)

    Article  CAS  ADS  Google Scholar 

  15. The Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061–1068 (2008)

    Article  Google Scholar 

  16. Weir, B. A. et al. Characterizing the cancer genome in lung adenocarcinoma. Nature 450, 893–898 (2007)

    Article  CAS  ADS  Google Scholar 

  17. Campbell, P. J. et al. Identification of somatically acquired rearrangements in cancer using genome-wide massively parallel paired-end sequencing. Nature Genet. 40, 722–729 (2008)

    Article  CAS  Google Scholar 

  18. Weterings, E. & Chen, D. J. The endless tale of non-homologous end-joining. Cell Res. 18, 114–124 (2008)

    Article  CAS  Google Scholar 

  19. van Gent, D. C. & van der Burg, M. Non-homologous end-joining, a sticky affair. Oncogene 26, 7731–7740 (2007)

    Article  CAS  Google Scholar 

  20. Hefferin, M. L. & Tomkinson, A. E. Mechanism of DNA double-strand break repair by non-homologous end joining. DNA Repair 4, 639–648 (2005)

    Article  CAS  Google Scholar 

  21. Hastings, P. J., Lupski, J. R., Rosenberg, S. M. & Ira, G. Mechanisms of change in gene copy number. Nature Rev. Genet. 10, 551–564 (2009)

    Article  CAS  Google Scholar 

  22. Yan, C. T. et al. IgH class switching and translocations use a robust non-classical end-joining pathway. Nature 449, 478–482 (2007)

    Article  CAS  ADS  Google Scholar 

  23. Bohlander, S. K. ETV6: a versatile player in leukemogenesis. Semin. Cancer Biol. 15, 162–174 (2005)

    Article  CAS  Google Scholar 

  24. Knezevich, S. R., McFadden, D. E., Tao, W., Lim, J. F. & Sorensen, P. H. A novel ETV6NTRK3 gene fusion in congenital fibrosarcoma. Nature Genet. 18, 184–187 (1998)

    Article  CAS  Google Scholar 

  25. Lannon, C. L. & Sorensen, P. H. ETV6–NTRK3: a chimeric protein tyrosine kinase with transformation activity in multiple cell lineages. Semin. Cancer Biol. 15, 215–223 (2005)

    Article  CAS  Google Scholar 

  26. Jones, D. T. et al. Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res. 68, 8673–8677 (2008)

    Article  CAS  Google Scholar 

  27. Basecke, J., Whelan, J. T., Griesinger, F. & Bertrand, F. E. The MLL partial tandem duplication in acute myeloid leukaemia. Br. J. Haematol. 135, 438–449 (2006)

    Article  Google Scholar 

  28. Blow, J. J. & Gillespie, P. J. Replication licensing and cancer—a fatal entanglement? Nature Rev. Cancer 8, 799–806 (2008)

    Article  CAS  Google Scholar 

  29. Perou, C. M. et al. Molecular portraits of human breast tumours. Nature 406, 747–752 (2000)

    Article  CAS  ADS  Google Scholar 

  30. Sorlie, T. et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc. Natl Acad. Sci. USA 98, 10869–10874 (2001)

    Article  CAS  ADS  Google Scholar 

  31. Chin, K. et al. Genomic and transcriptional aberrations linked to breast cancer pathophysiologies. Cancer Cell 10, 529–541 (2006)

    Article  CAS  Google Scholar 

  32. Bergamaschi, A. et al. Distinct patterns of DNA copy number alteration are associated with different clinicopathological features and gene-expression subtypes of breast cancer. Genes Chromosom. Cancer 45, 1033–1040 (2006)

    Article  CAS  Google Scholar 

  33. Li, H., Ruan, J. & Durbin, R. Mapping short DNA sequencing reads and calling variants using mapping quality scores. Genome Res. 18, 1851–1858 (2008)

    Article  CAS  Google Scholar 

  34. Ning, Z., Cox, A. J. & Mullikin, J. C. SSAHA: a fast search method for large DNA databases. Genome Res. 11, 1725–1729 (2001)

    Article  CAS  Google Scholar 

  35. Venkatraman, E. & Olshen, A. A faster circular binary segmentation algorithm for the analysis of array CGH data. Bioinformatics 23, 657–663 (2007)

    Article  CAS  Google Scholar 

  36. Lambros, M. et al. Unlocking pathology archives for molecular genetic studies: a reliable method to generate probes for chromogenic and fluorescent in situ hybridization. Lab. Invest. 86, 398–408 (2006)

    Article  CAS  Google Scholar 

  37. Abeysinghe, S. S. et al. Translocation and gross deletion breakpoints in human inherited disease and cancer I: Nucleotide composition and recombination-associated motifs. Hum. Mutat. 22, 229–244 (2003)

    Article  CAS  Google Scholar 

  38. Scholz, F. W. & Stephens, M. A. K-sample Anderson-Darling tests. Am. J. Stat. Assoc. 82, 918–924 (1987)

    MathSciNet  Google Scholar 

Download references

Acknowledgements

We are grateful to M. Lambros, F. Geyer and R. Vatcheva for their assistance in the FISH experiments. We would like to acknowledge the support of the Kay Kendall Leukaemia Fund under Grant KKL282, Human Frontiers Award reference LT000561/2009-L, the Dana-Farber/Harvard SPORE in breast cancer under NCI grant reference CA089393, Breakthrough Breast Cancer, the Research Council of Norway Grants no. 155218 and 175240, and the Wellcome Trust under grant reference 077012/Z/05/Z.

Author Contributions M.R.S., P.A.F., P.J.C. and P.J.S. designed the experiment. S.E., D.J.M., P.J.S., M-L.L., I.V., L.J.M., J.B., M.A.Q., H.S., C.C., R.N., A.M.S., A.L., J.W.M.M. and C.Latimer carried out laboratory analyses. J.A.F., J.S.R.-F., L.v.V., A.L.R. D.P.S. and A.-L.B.-D. provided clinical samples. P.J.S., D.J.M., I.V., M.-L.L., E.D.P., J.T.S., L.A.S., C.Leroy, C.D.G., M.J., J.W.T., K.W.L., P.J.C., P.A.F., J.S.R.-F., J.W.M.M., A.M.S., J.A.F., M.R.S., H.E.G.R., A.L.R., A.-L.B.-D., L.v.V., A.L., P.J.C. and P.A.F. performed data analysis, informatics and statistics. M.R.S. wrote the manuscript with comments from P.J.S., P.A.F., P.J.C., A.-L.B.-D., J.S.R.-F., J.A.F., A.L.R., D.P.S. and L.v.V.

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Correspondence to P. Andrew Futreal or Michael R. Stratton.

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Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1-7 with Legends. (PDF 5501 kb)

Supplementary Table 1

Summary of somatic rearrangements found in 24 breast cancers (XLS 845 kb)

Supplementary Table 2

Variation in the prevalence of rearrangement architectures in individual breast cancer genomes. (XLS 28 kb)

Supplementary Table 3

Base pair resolution of rearrangement breakpoints. (XLS 350 kb)

Supplementary Table 4

GC content analysis at rearrangement breakpoints. (XLS 22 kb)

Supplementary Table 5

Evaluation of motif enrichment at rearrangement breakpoints. (XLS 24 kb)

Supplementary Table 6

Gene Fusions. (PDF 135 kb)

Supplementary Table 7

Internally rearranged genes. (XLS 69 kb)

Supplementary Table 8

Known cancer genes that are rearranged. (XLS 36 kb)

Supplementary Table 9

Rearranged genes. (XLS 452 kb)

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Stephens, P., McBride, D., Lin, ML. et al. Complex landscapes of somatic rearrangement in human breast cancer genomes. Nature 462, 1005–1010 (2009). https://doi.org/10.1038/nature08645

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