Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Oncogenomics
  • Published:

Genome-wide DNA copy number analysis in pancreatic cancer using high-density single nucleotide polymorphism arrays

Oncogene volume 27, pages 1951–1960 (2008)Cite this article

Abstract

To identify genomic abnormalities characteristic of pancreatic ductal adenocarcinoma (PDAC) in vivo, a panel of 27 microdissected PDAC specimens were analysed using high-density microarrays representing ∼116 000 single nucleotide polymorphism (SNP) loci. We detected frequent gains of 1q, 2, 3, 5, 7p, 8q, 11, 14q and 17q (⩾78% of cases), and losses of 1p, 3p, 6, 9p, 13q, 14q, 17p and 18q (⩾44%). Although the results were comparable with those from array CGH, regions of those genetic changes were defined more accurately by SNP arrays. Integrating the Ensembl public data, we have generated ‘gene’ copy number indices that facilitate the search for novel candidates involved in pancreatic carcinogenesis. Copy numbers in a subset of the genes were validated using quantitative real-time PCR. The SKAP2/SCAP2 gene (7p15.2), which belongs to the src family kinases, was most frequently (63%) amplified in our sample set and its recurrent overexpression (67%) was confirmed by reverse transcription–PCR. Furthermore, fluorescence in situ hybridization and in situ RNA hybridization analyses for this gene have demonstrated a significant correlation between DNA copy number and mRNA expression level in an independent sample set (P<0.001). These findings indicate that the dysregulation of SKAP2/SCAP2, which is mostly caused by its increased gene copy number, is likely to be associated with the development of PDAC.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

Abbreviations

array CGH:

array-based comparative genomic hybridization

DCN:

DNA copy number

FISH:

fluorescence in situ hybridization

ISH:

in situ RNA hybridization

LOH:

loss of heterozygosity

PDAC:

pancreatic ductal adenocarcinoma

q-PCR:

quantitative real-time PCR

RT–PCR:

reverse transcription–PCR

SNP:

single nucleotide polymorphism

UPD:

uniparental disomy

References

  • Andersen CL, Wiuf C, Kruhoffer M, Korsgaard M, Laurberg S, Orntoft TF . (2007). Frequent occurrence of uniparental disomy in colorectal cancer. Carcinogenesis 28: 38–48.

    Article  CAS  PubMed  Google Scholar 

  • Bardeesy N, DePinho RA . (2002). Pancreatic cancer biology and genetics. Nat Rev Cancer 2: 897–909.

    Article  CAS  PubMed  Google Scholar 

  • Bignell GR, Huang J, Greshock J, Watt S, Butler A, West S et al. (2004). High-resolution analysis of DNA copy number using oligonucleotide microarrays. Genome Res 14: 287–295.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Buchholz M, Braun M, Heidenblut A, Kestler HA, Kloppel G, Schmiegel W et al. (2005). Transcriptome analysis of microdissected pancreatic intraepithelial neoplastic lesions. Oncogene 24: 6626–6636.

    Article  CAS  PubMed  Google Scholar 

  • Calhoun ES, Hucl T, Gallmeier E, West KM, Arking DE, Maitra A et al. (2006). Identifying allelic loss and homozygous deletions in pancreatic cancer without matched normals using high-density single-nucleotide polymorphism arrays. Cancer Res 66: 7920–7928.

    Article  CAS  PubMed  Google Scholar 

  • Chin K, DeVries S, Fridlyand J, Spellman PT, Roydasgupta R, Kuo WL et al. (2006). Genomic and transcriptional aberrations linked to breast cancer pathophysiologies. Cancer Cell 10: 529–541.

    Article  CAS  PubMed  Google Scholar 

  • Fitzgibbon J, Smith LL, Raghavan M, Smith ML, Debernardi S, Skoulakis S et al. (2005). Association between acquired uniparental disomy and homozygous gene mutation in acute myeloid leukemias. Cancer Res 65: 9152–9154.

    Article  CAS  PubMed  Google Scholar 

  • Fujita M, Sugama S, Nakai M, Takenouchi T, Wei J, Urano T et al. (2006). Alpha-synuclein stimulates differentiation of osteosarcoma cells: Relevance to downregulation of proteasome activity. J Biol Chem 282: 5736–5748.

    Article  PubMed  Google Scholar 

  • Griffin CA, Hruban RH, Morsberger LA, Ellingham T, Long PP, Jaffee EM et al. (1995). Consistent chromosome abnormalities in adenocarcinoma of the pancreas. Cancer Res 55: 2394–2399.

    CAS  PubMed  Google Scholar 

  • Harada T, Baril P, Gangeswaran R, Kelly G, Chelala C, Bhakta V et al. (2007). Identification of genetic alterations in pancreatic cancer by the combined use of tissue microdissection and array-based comparative genomic hybridisation. Br J Cancer 96: 373–382.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Harada T, Okita K, Shiraishi K, Kusano N, Furuya T, Oga A et al. (2002a). Detection of genetic alterations in pancreatic cancers by comparative genomic hybridization coupled with tissue microdissection and degenerate oligonucleotide primed polymerase chain reaction. Oncology 62: 251–258.

    Article  CAS  PubMed  Google Scholar 

  • Harada T, Okita K, Shiraishi K, Kusano N, Kondoh S, Sasaki K . (2002b). Interglandular cytogenetic heterogeneity detected by comparative genomic hybridization in pancreatic cancer. Cancer Res 62: 835–839.

    CAS  PubMed  Google Scholar 

  • Huang J, Wei W, Zhang J, Liu G, Bignell GR, Stratton MR et al. (2004). Whole genome DNA copy number changes identified by high density oligonucleotide arrays. Hum Genomics 1: 287–299.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Iacobuzio-Donahue CA, van der Heijden MS, Baumgartner MR, Troup WJ, Romm JM, Doheny K et al. (2004). Large-scale allelotype of pancreaticobiliary carcinoma provides quantitative estimates of genome-wide allelic loss. Cancer Res 64: 871–875.

    Article  CAS  PubMed  Google Scholar 

  • Iafrate AJ, Feuk L, Rivera MN, Listewnik ML, Donahoe PK, Qi Y et al. (2004). Detection of large-scale variation in the human genome. Nat Genet 36: 949–951.

    Article  CAS  PubMed  Google Scholar 

  • Janne PA, Li C, Zhao X, Girard L, Chen TH, Minna J et al. (2004). High-resolution single-nucleotide polymorphism array and clustering analysis of loss of heterozygosity in human lung cancer cell lines. Oncogene 23: 2716–2726.

    Article  PubMed  Google Scholar 

  • Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A et al. (2005). Cancer statistics, 2005. CA Cancer J Clin 55: 10–30.

    Article  PubMed  Google Scholar 

  • Karhu R, Mahlamaki E, Kallioniemi A . (2006). Pancreatic adenocarcinoma—genetic portrait from chromosomes to microarrays. Genes Chromosomes Cancer 45: 721–730.

    Article  CAS  PubMed  Google Scholar 

  • Li D, Xie K, Wolff R, Abbruzzese JL . (2004). Pancreatic cancer. Lancet 363: 1049–1057.

    Article  CAS  PubMed  Google Scholar 

  • Lindblad-Toh K, Tanenbaum DM, Daly MJ, Winchester E, Lui WO, Villapakkam A et al. (2000). Loss-of-heterozygosity analysis of small-cell lung carcinomas using single-nucleotide polymorphism arrays. Nat Biotechnol 18: 1001–1005.

    Article  CAS  PubMed  Google Scholar 

  • Lips EH, de Graaf EJ, Tollenaar RAEM, van Eijk R, Oosting J, Szuhai K et al. (2007). Single nucleotide polymorphism array analysis of chromosomal instability patterns discriminates rectal adenomas from carcinomas. J Pathol 212: 269–277.

    Article  CAS  PubMed  Google Scholar 

  • McLean GW, Carragher NO, Avizienyte E, Evans J, Brunton VG, Frame MC . (2005). The role of focal-adhesion kinase in cancer—a new therapeutic opportunity. Nat Rev Cancer 5: 505–515.

    Article  CAS  PubMed  Google Scholar 

  • Midorikawa Y, Yamamoto S, Ishikawa S, Kamimura N, Igarashi H, Sugimura H et al. (2006). Molecular karyotyping of human hepatocellular carcinoma using single-nucleotide polymorphism arrays. Oncogene 25: 5581–5590.

    Article  CAS  PubMed  Google Scholar 

  • Nannya Y, Sanada M, Nakazaki K, Hosoya N, Wang L, Hangaishi A et al. (2005). A robust algorithm for copy number detection using high-density oligonucleotide single nucleotide polymorphism genotyping arrays. Cancer Res 65: 6071–6079.

    Article  CAS  PubMed  Google Scholar 

  • Raghavan M, Lillington DM, Skoulakis S, Debernardi S, Chaplin T, Foot NJ et al. (2005). Genome-wide single nucleotide polymorphism analysis reveals frequent partial uniparental disomy due to somatic recombination in acute myeloid leukemias. Cancer Res 65: 375–378.

    CAS  PubMed  Google Scholar 

  • Redon R, Ishikawa S, Fitch KR, Feuk L, Perry GH, Andrews TD et al. (2006). Global variation in copy number in the human genome. Nature 444: 444–454.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ried T, Heselmeyer-Haddad K, Blegen H, Schrock E, Auer G . (1999). Genomic changes defining the genesis, progression, and malignancy potential in solid human tumors: a phenotype/genotype correlation. Genes Chromosomes Cancer 25: 195–204.

    Article  CAS  PubMed  Google Scholar 

  • Saramaki OR, Porkka KP, Vessella RL, Visakorpi T . (2006). Genetic aberrations in prostate cancer by microarray analysis. Int J Cancer 119: 1322–1329.

    Article  CAS  PubMed  Google Scholar 

  • Takahashi T, Yamashita H, Nagano Y, Nakamura T, Ohmori H, Avraham H et al. (2003). Identification and characterization of a novel Pyk2/related adhesion focal tyrosine kinase-associated protein that inhibits alpha-synuclein phosphorylation. J Biol Chem 278: 42225–42233.

    Article  CAS  PubMed  Google Scholar 

  • Yamamoto G, Nannya Y, Kato M, Sanada M, Levine RL, Kawamata N et al. (2007). Highly sensitive method for genome-wide detection of allelic composition in nonpaired, primary tumor specimens by use of Affymetrix single-nucleotide–polymorphism genotyping microarrays. Am J Hum Genet 81: 114–126.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao X, Li C, Paez JG, Chin K, Janne PA, Chen TH et al. (2004). An integrated view of copy number and allelic alterations in the cancer genome using single nucleotide polymorphism arrays. Cancer Res 64: 3060–3071.

    Article  CAS  PubMed  Google Scholar 

  • Zhao X, Weir BA, LaFramboise T, Lin M, Beroukhim R, Garraway L et al. (2005). Homozygous deletions and chromosome amplifications in human lung carcinomas revealed by single nucleotide polymorphism array analysis. Cancer Res 65: 5561–5570.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by Cancer Research UK (C355/A6254). We thank Professor Kiwamu Okita (Department of Gastroenterology and Hepatology, Yamaguchi University School of Medicine) for providing clinical samples of PDAC.

Author information

Authors and Affiliations

  1. Centre for Molecular Oncology, Cancer Research UK, Institute of Cancer, Barts and The London School of Medicine and Dentistry, Queen Mary, University of London, London, UK

    T Harada, C Chelala, V Bhakta, K Caulee, P Baril & N R Lemoine

  2. Centre for Medical Oncology, Cancer Research UK, Institute of Cancer, Barts and The London School of Medicine and Dentistry, Queen Mary, University of London, London, UK

    T Chaplin & B D Young

Authors
  1. T Harada
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C Chelala
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. V Bhakta
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. T Chaplin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. K Caulee
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. P Baril
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. B D Young
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. N R Lemoine
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to N R Lemoine.

Additional information

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

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Harada, T., Chelala, C., Bhakta, V. et al. Genome-wide DNA copy number analysis in pancreatic cancer using high-density single nucleotide polymorphism arrays. Oncogene 27, 1951–1960 (2008). https://doi.org/10.1038/sj.onc.1210832

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210832

Keywords

This article is cited by

Search

Advanced search

Quick links