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Interphase chromosome folding determines spatial proximity of genes participating in carcinogenic RET/PTC rearrangements

Oncogene volume 25, pages 2360–2366 (2006)Cite this article

Abstract

Recurrent chromosomal rearrangements are common in cancer cells and may be influenced by nonrandom positioning of recombination-prone genetic loci in the nucleus. However, the mechanism responsible for spatial proximity of specific loci is unknown. In this study, we use an 18 Mb region on 10q11.2–21 containing the RET gene and its recombination partners, the H4 and NCOA4 (ELE1) genes, as a model chromosomal region frequently involved in RET/PTC rearrangements in thyroid cancer. RET/PTC is particularly common in tumors from children exposed to ionizing radiation. Using fluorescence in situ hybridization and three-dimensional microscopy, the locations of five different loci in this region were mapped in interphase nuclei of normal human thyroid cells. We show that RET and NCOA4 are much closer to each other than expected based on their genomic separation. Modeling of chromosome folding in this region suggests the presence of chromosome coiling with coils of ∼8 Mb in length, which positions the RET gene close to both, the NCOA4 and H4, loci. There was no significant variation in gene proximity between adult and pediatric thyroid cells. This study provides evidence for large-scale chromosome folding of the 10q11.2–21 region that offers a structural basis for nonrandom positioning and spatial proximity of potentially recombinogenic intrachromosomal loci.

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Acknowledgements

We are grateful to H-UG Weier and JW Gray for providing PAC clone RMC10P016, to Ganesh Srinivasan and Bharath Arunachalam for technical assistance, and to Dave Campbell for assistance with creating the animation. Supported by NIH Grant CA88041.

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    M Gandhi & Y E Nikiforov

  2. Center for Biostatistical Services, University of Cincinnati College of Medicine, OH, USA

    M Medvedovic

  3. Division of Biomedical Informatics, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH, USA

    M Medvedovic

  4. Department of Molecular Genetics, University of Cincinnati College of Medicine, OH, USA

    J R Stringer

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  1. M Gandhi
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  2. M Medvedovic
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  3. J R Stringer
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  4. Y E Nikiforov
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Correspondence to Y E Nikiforov.

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Supplementary Information accompanies the paper on Oncogene website (http://www.nature.com/onc).

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Gandhi, M., Medvedovic, M., Stringer, J. et al. Interphase chromosome folding determines spatial proximity of genes participating in carcinogenic RET/PTC rearrangements. Oncogene 25, 2360–2366 (2006). https://doi.org/10.1038/sj.onc.1209268

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