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Genome scanning with array CGH delineates regional alterations in mouse islet carcinomas

Nature Genetics volume 29, pages 459–464 (2001)Cite this article

A Correction to this article was published on 01 December 2001

Abstract

Carcinomas that develop in the pancreatic islets of transgenic mice expressing the SV40 T-antigens (Tag) under transcriptional control of the rat insulin II promoter (RIP) progress through well-characterized stages that are similar to aspects of human tumor progression, including hyperplastic growth, increased angiogenesis and reduced apoptosis1. The latter two stages have been associated with recurrent loss of heterozygosity (LOH)2 and reduced genome copy number3 on chromosomes 9 (LOH9) and 16 (LOH16), aberrations which we believe contribute to these phenotypes. Earlier analyses localized LOH9 to approximately 3 Mb and LOH16 to approximately 30 Mb (both syntenic with human 3q21–q25) but were limited by low throughput and a lack of informative polymorphic markers. Here we show that comparative genomic hybridization to DNA microarrays (array CGH)4,5,6,7 overcomes these limitations by allowing efficient, genome-wide analyses of relative genome copy number. The CGH arrays used in these experiments carried BACs distributed at 2–20-MB intervals across the mouse genome and at higher density in regions of interest. Using array CGH, we further narrowed the loci for LOH9 and LOH16 and defined new or previously unappreciated recurrent regions of copy-number decrease on chromosomes 6, 8 and 14 (syntenic with human chromosomes 12p11–p13, 16q24.3 and 13q11–q32, respectively) and regions of copy-number increase on chromosomes 2 and 4 (syntenic to human chromosomes 20q13.2 and 1p32–p36, respectively). Our analyses of human genome sequences syntenic to these regions suggest that CYP24, PFDN4, STMN1, CDKN1B, PPP2R3 and FSTL1 are candidate oncogenes or tumor-suppressor genes. We also show that irradiation and genetic background influence the spectrum of aberrations present in these tumors.

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Figure 1: CGH analyses of genome copy number in murine tissues, tumors and cell lines.
Figure 2: Influence of normal genomic DNA contamination on detecting single copy-number abnormalities in tumors.
Figure 3: Frequency of occurrence of regions of aberration observed in 85 RIP-Tag tumors.
Figure 4: Identification of chromosome 16 interstitial deletions by array CGH delimits LOH16.
Figure 5: Genome Cryptographer annotation of human genomic sequence syntenic to the region of chromosome 9 loss encoding the apoptotic regulator PPP2R3.

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Acknowledgements

This study was supported by USPHS grants CA78601 and R37-CA45234 and by the UCSF Comprehensive Cancer Center Core Grant (CA82103).

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Authors and Affiliations

  1. Cancer Genetics and Breast Oncology Programs, UCSF Cancer Center, University of California at San Francisco, Box 0808, San Francisco, 94143-0808, California, USA

    Graeme Hodgson, Stas Volik, Sujatmi Hariono, Meredith Wernick, Dan Moore, Donna G. Albertson, Daniel Pinkel, Colin Collins & Joe W. Gray

  2. Department of Laboratory Medicine, University of California at San Francisco, Box 0808, San Francisco, 94143-0808, California, USA

    Donna G. Albertson, Daniel Pinkel, Colin Collins & Joe W. Gray

  3. Department of Biochemistry and Biophysics, UCSF Diabetes and Comprehensive Cancer Centers, University of California at San Francisco, San Francisco, 94143-0534, California, USA

    Jeffrey H. Hager & Douglas Hanahan

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  1. Graeme Hodgson
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Correspondence to Joe W. Gray.

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Hodgson, G., Hager, J., Volik, S. et al. Genome scanning with array CGH delineates regional alterations in mouse islet carcinomas. Nat Genet 29, 459–464 (2001). https://doi.org/10.1038/ng771

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