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Identification of novel CHD1-associated collaborative alterations of genomic structure and functional assessment of CHD1 in prostate cancer

Oncogene volume 31, pages 3939–3948 (2012)Cite this article

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Abstract

A clearer definition of the molecular determinants that drive the development and progression of prostate cancer (PCa) is urgently needed. Efforts to map recurrent somatic deletions in the tumor genome, especially homozygous deletions (HODs), have provided important positional information in the search for cancer-causing genes. Analyzing HODs in the tumors of 244 patients from two independent cohorts and 22 PCa xenografts using high-resolution single-nucleotide polymorphism arrays, herein we report the identification of CHD1, a chromatin remodeler, as one of the most frequently homozygously deleted genes in PCa, second only to PTEN in this regard. The HODs observed in CHD1, including deletions affecting only internal exons of CHD1, were found to completely extinguish the expression of mRNA of this gene in PCa xenografts. Loss of this chromatin remodeler in clinical specimens is significantly associated with an increased number of additional chromosomal deletions, both hemi- and homozygous, especially on 2q, 5q and 6q. Together with the deletions observed in HEK293 cells stably transfected with CHD1 small hairpin RNA, these data suggest a causal relationship. Downregulation of Chd1 in mouse prostate epithelial cells caused dramatic morphological changes indicative of increased invasiveness, but did not result in transformation. Indicating a new role of CHD1, these findings collectively suggest that distinct CHD1-associated alterations of genomic structure evolve during and are required for the development of PCa.

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Acknowledgements

The study is partially supported by the National Institutes of Health Grants CA135008 and CA133066 (to W Liu and WB Isaacs), CA119069 (to J Xu), CA131338 and 133009 (to SL Zheng and WB Isaacs). We thank Tamara Adams for editing the manuscript. The support of William T Gerrard, Mario Duhon, Jennifer and John Chalsty and P Kevin Jaffe (to WBI) is gratefully acknowledged.

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Authors and Affiliations

  1. Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, NC, USA

    W Liu, T Li, C Xie, S-T Kim, Z Wang, A R Turner, Z Zhang, J Feng, J Sun, S L Zheng & J Xu

  2. Center for Human Genomics and Personalized Medicine Research, Wake Forest University School of Medicine, Winston-Salem, NC, USA

    W Liu, T Li, C Xie, S-T Kim, Z Wang, A R Turner, Z Zhang, J Feng, J Sun, S L Zheng & J Xu

  3. Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden

    J Lindberg & H Grönberg

  4. Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA

    G Sui, M Wan & S D Cramer

  5. Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA

    J Luo, C M Ewing, G Yan, M Gielzak & W B Isaacs

  6. Department of Pathology and Cytology, Karolinska University Hospital, Stockholm, Sweden

    L Egevad

  7. Center for Genetic Epidemiology and Prevention, Van Andel Research Institute, Grand Rapids, MI, USA

    Y Yan & J Xu

  8. Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA

    G S Bova

  9. Department of Urology, University of Washington, Seattle, WA, USA

    R L Vessella

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  1. W Liu
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Correspondence to W B Isaacs or J Xu.

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Liu, W., Lindberg, J., Sui, G. et al. Identification of novel CHD1-associated collaborative alterations of genomic structure and functional assessment of CHD1 in prostate cancer. Oncogene 31, 3939–3948 (2012). https://doi.org/10.1038/onc.2011.554

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