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Regional copy number–independent deregulation of transcription in cancer

Nature Genetics volume 38, pages 1386–1396 (2006)Cite this article

A Corrigendum to this article was published on 01 March 2008

This article has been updated

Abstract

Genetic and epigenetic alterations have been identified that lead to transcriptional deregulation in cancers. Genetic mechanisms may affect single genes or regions containing several neighboring genes, as has been shown for DNA copy number changes. It was recently reported that epigenetic suppression of gene expression can also extend to a whole region; this is known as long-range epigenetic silencing. Various techniques are available for identifying regional genetic alterations, but no large-scale analysis has yet been carried out to obtain an overview of regional epigenetic alterations. We carried out an exhaustive search for regions susceptible to such mechanisms using a combination of transcriptome correlation map analysis and array CGH data for a series of bladder carcinomas. We validated one candidate region experimentally, demonstrating histone methylation leading to the loss of expression of neighboring genes without DNA methylation.

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Figure 1: Transcriptome correlation map of chromosome 8 for the 57 bladder carcinomas.
Figure 2: Comparison of CGH array data and transcriptome correlation maps: identification of regions of correlation due to DNA copy number changes.
Figure 3: Scatter plots of Affymetrix signal versus CGH log2 ratio for the EIF3S9, SHOC2 and ASH2L genes.
Figure 4: Comparison of CGH array data and transcriptome correlation maps: identification of regions of correlation not due to DNA copy number changes.
Figure 5: Delimitation of the 3-2 region by transcriptome and genome analyses.
Figure 6: Experimental validation of the 3-2 region.

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  • 27 February 2008

    In the version of this article initially published, the horizontal dashed lines representing the threshold value in the panels in row b of Figures 2 and 4 were incorrectly placed. The errors have been corrected in the HTML and PDF versions of this article.

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Acknowledgements

We thank C. Rouveirol for discussions, P. Hupé for his GLAD algorithm expertise and the Institut Curie Bioinformatics Service headed by E. Barillot for support. We also thank J. Sappa from Alex Edelman & Associates for careful reading of the manuscript and the UCSF Cancer Center Array CGH Core for providing the BAC arrays. This article is dedicated to the memory of D. Chopin, whose commitment to cancer research was of paramount importance for the initiation of this work. This work was supported by the CNRS, the Institut Curie, AstraZeneca, the Canceropole Ile de France and the Ligue Nationale Contre le Cancer. N.S., C.V., F. Reyal, I.B.-P., S.G.D. de M. and F. Radvanyi are members of the Equipe Oncologie Moléculaire, labellisée par La Ligue Nationale Contre le Cancer. N.S. was supported by a fellowship from the French Ministry of Education and Research and a fellowship from the Association pour la Recherche sur le Cancer. C.V. was supported by a fellowship from the French Ministry of Education and Research and F. Reyal by a fellowship from the Ligue Nationale Contre le Cancer.

Author information

Author notes

  1. Dominique K Chopin: Deceased.

  2. Nicolas Stransky and Céline Vallot: These authors contributed equally to this work.

Authors and Affiliations

  1. UMR 144 Centre National de la Recherche Scientifique (CNRS)/Institut Curie, Paris, 75248 Cedex 05, France

    Nicolas Stransky, Céline Vallot, Fabien Reyal, Isabelle Bernard-Pierrot, Sixtina Gil Diez de Medina, Jean Paul Thiery & François Radvanyi

  2. EMI Institut National de la Santé et de la Recherche Médicale (INSERM) 03-37, Hôpital Henri Mondor, Créteil, 94010, Cedex, France

    Sixtina Gil Diez de Medina, Yves Allory, Claude C Abbou & Dominique K Chopin

  3. Comprehensive Cancer Center, University of California San Francisco (UCSF), San Francisco, 94143, California, USA

    Rick Segraves, Donna G Albertson & Daniel Pinkel

  4. Department of Biostatistics, Institut Curie, Paris, 75248 Cedex 05, France

    Yann de Rycke & Bernard Asselain

  5. Cancer and Infection Research Area, AstraZeneca, Mereside, Alderley Park, Macclesfield, SK10 4TG, Cheshire, UK

    Paul Elvin, Andrew Cassidy, Carolyn Spraggon & Alexander Graham

  6. Department of Biology, Jack Birch Unit of Molecular Carcinogenesis, University of York, Heslington, YO10 5DD, York, UK

    Jennifer Southgate

  7. Department of Pathology, Hôpital Henri Mondor, Créteil, 94010, Cedex, France

    Yves Allory

  8. Department of Urology, Hôpital Henri Mondor, Créteil, 94010, Cedex, France

    Claude C Abbou & Dominique K Chopin

  9. Cancer Research Institute, UCSF, San Francisco, 94143, California, USA

    Donna G Albertson

  10. Department of Translational Research, Institut Curie, Paris, 75248, Cedex 05, France

    Jean Paul Thiery

  11. Institute of Molecular and Cell Biology, Proteos, 138673, Singapore

    Jean Paul Thiery

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Supplementary information

Supplementary Fig. 1

Transcriptome correlation maps of all chromosomes for the 57 bladder carcinomas. (PDF 1711 kb)

Supplementary Fig. 2

Quantitative PCR analysis of the gene copy number of region 3-2. (PDF 33 kb)

Supplementary Table 1

Transcriptome correlation map of 57 bladder carcinomas for chromosomes 1 to X (PDF 130 kb)

Supplementary Table 2

Clinical data of the 57 bladder carcinomas. (PDF 42 kb)

Supplementary Table 3

Primers for quantitative PCR, COBRA and ChIP experiments. (PDF 45 kb)

Supplementary Note (PDF 42 kb)

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Stransky, N., Vallot, C., Reyal, F. et al. Regional copy number–independent deregulation of transcription in cancer. Nat Genet 38, 1386–1396 (2006). https://doi.org/10.1038/ng1923

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