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Array comparative genomic hybridization and its applications in cancer

Abstract

Alteration in DNA copy number is one of the many ways in which gene expression and function may be modified. Some variations are found among normal individuals, others occur in the course of normal processes in some species and still others participate in causing various disease states. For example, many defects in human development are due to gains and losses of chromosomes and chromosomal segments that occur before or shortly after fertilization, and DNA dosage-alteration changes occurring in somatic cells are frequent contributors to cancer. Detecting these aberrations and interpreting them in the context of broader knowledge facilitates the identification of crucial genes and pathways involved in biological processes and disease. Over the past several years, array comparative genomic hybridization has proven its value for analyzing DNA copy-number variations. Here, we discuss the state of the art of array comparative genomic hybridization and its applications in cancer, emphasizing general concepts rather than specific results.

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Figure 1: Overview of array CGH.
Figure 2: Factors influencing the success of array CGH.
Figure 3: Array CGH analysis of a deletion boundary using arrays with elements of different complexity.
Figure 4: Relationship of measured ratios to copy-number change.

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References

  1. Kallioniemi, A. et al. Comparative genomic hybridization for molecular cytogenetic analysis of solid tumors. Science 258, 818–821 (1992).

    Article  CAS  PubMed  Google Scholar 

  2. du Manoir, S. et al. Detection of complete and partial chromosome gains and losses by comparative genomic in situ hybridization. Hum. Genet. 90, 590–610 (1993).

    Article  CAS  PubMed  Google Scholar 

  3. Karhu, R., Rummukainen, J., Lorch, T. & Isola, J. Four-color CGH: a new method for quality control of comparative genomic hybridization. Genes Chromosomes Cancer 24, 112–118 (1999).

    Article  CAS  PubMed  Google Scholar 

  4. Mohapatra, G. et al. Analyses of brain tumor cell lines confirm a simple model of relationships among fluorescence in situ hybridization, DNA index, and comparative genomic hybridization. Genes Chromosomes Cancer 20, 311–319 (1997).

    Article  CAS  PubMed  Google Scholar 

  5. Solinas-Toldo, S. et al. Matrix-based comparative genomic hybridization: biochips to screen for genomic imbalances. Genes Chromosomes Cancer 20, 399–407 (1997).

    Article  CAS  PubMed  Google Scholar 

  6. Pinkel, D. et al. High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays. Nat. Genet. 20, 207–211 (1998).

    Article  CAS  PubMed  Google Scholar 

  7. Snijders, A.M. et al. Assembly of microarrays for genome-wide measurement of DNA copy number. Nat. Genet. 29, 263–264 (2001).

    Article  CAS  PubMed  Google Scholar 

  8. Hodgson, G. et al. Genome scanning with array CGH delineates regional alterations in mouse islet carcinomas. Nat. Genet. 29, 459–464 (2001).

    Article  CAS  PubMed  Google Scholar 

  9. Fiegler, H. et al. DNA microarrays for comparative genomic hybridization based on DOP-PCR amplification of BAC and PAC clones. Genes Chromosomes Cancer 36, 361–374 (2003).

    Article  CAS  PubMed  Google Scholar 

  10. Smirnov, D.A., Burdick, J.T., Morley, M. & Cheung, V.G. Method for manufacturing whole-genome microarrays by rolling circle amplification. Genes Chromosomes Cancer 40, 72–77 (2004).

    Article  CAS  PubMed  Google Scholar 

  11. Ishkanian, A.S. et al. A tiling resolution DNA microarray with complete coverage of the human genome. Nat. Genet. 36, 299–303 (2004).

    Article  CAS  PubMed  Google Scholar 

  12. Li, J. et al. Genomic segmental polymorphisms in inbred mouse strains. Nat. Genet. 36, 952–954 (2004).

    Article  CAS  PubMed  Google Scholar 

  13. Pollack, J.R. et al. Genome-wide analysis of DNA copy-number changes using cDNA microarrays. Nat. Genet. 23, 41–46 (1999).

    Article  CAS  PubMed  Google Scholar 

  14. Mantripragada, K.K. et al. DNA copy-number analysis of the 22q11 deletion-syndrome region using array-CGH with genomic and PCR-based targets. Int. J. Mol. Med. 13, 273–279 (2004).

    CAS  PubMed  Google Scholar 

  15. Dhami, P. et al. Exon array-CGH: detection of copy number changes at the resolution of individual exons in the human genome. Am. J. Hum. Genet. 76, 750–762 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Brennan, C. et al. High-resolution global profiling of genomic alterations with long oligonucleotide microarray. Cancer Res. 64, 4744–4748 (2004).

    Article  CAS  PubMed  Google Scholar 

  17. Carvalho, B., Ouwerkerk, E., Meijer, G.A. & Ylstra, B. High resolution microarray comparative genomic hybridisation analysis using spotted oligonucleotides. J. Clin. Pathol. 57, 644–646 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lucito, R. et al. Detecting gene copy number fluctuations in tumor cells by microarray analysis of genomic representations. Genome Res. 10, 1726–1736 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zhao, X. et al. An integrated view of copy number and allelic alterations in the cancer genome using single nucleotide polymorphism arrays. Cancer Res. 64, 3060–3071 (2004).

    Article  CAS  PubMed  Google Scholar 

  20. Zhou, X., Mok, S.C., Chen, Z., Li, Y. & Wong, D.T. Concurrent analysis of loss of heterozygosity (LOH) and copy number abnormality (CNA) for oral premalignancy progression using the Affymetrix 10K SNP mapping array. Hum. Genet. 115, 327–330 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. Pinkel, D. & Albertson, D. Array comparative genomic hybridization. Ann. Rev. Genet. Genomics (in the press).

  22. Fukiya, S., Mizoguchi, H., Tobe, T. & Mori, H. Extensive genomic diversity in pathogenic Escherichia coli and Shigella strains revealed by comparative genomic hybridization microarray. J. Bacteriol. 186, 3911–3921 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Watanabe, T., Murata, Y., Oka, S. & Iwahashi, H. A new approach to species determination for yeast strains: DNA microarray-based comparative genomic hybridization using a yeast DNA microarray with 6000 genes. Yeast 21, 351–365 (2004).

    Article  CAS  PubMed  Google Scholar 

  24. Albertson, D.G. et al. Quantitative mapping of amplicon structure by array CGH identifies CYP24 as a candidate oncogene. Nat. Genet. 25, 144–146 (2000).

    Article  CAS  PubMed  Google Scholar 

  25. Sebat, J. et al. Large-scale copy number polymorphism in the human genome. Science 305, 525–528 (2004).

    Article  CAS  PubMed  Google Scholar 

  26. Barrett, M.T. et al. Comparative genomic hybridization using oligonucleotide microarrays and total genomic DNA. Proc. Natl. Acad. Sci. USA 101, 17765–17770 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wang, N.J., Liu, D., Parokonny, A.S. & Schanen, N.C. High-resolution molecular characterization of 15q11-q13 rearrangements by array comparative genomic hybridization (array CGH) with detection of gene dosage. Am. J. Hum. Genet. 75, 267–281 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Lupski, J.R., Roth, J.R. & Weinstock, G.M. Chromosomal duplications in bacteria, fruit flies, and humans. Am. J. Hum. Genet. 58, 21–27 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Eichler, E.E. Segmental duplications: what's missing, misassigned, and misassembled– and should we care? Genome Res. 11, 653–656 (2001).

    Article  CAS  PubMed  Google Scholar 

  30. Emanuel, B.S. & Shaikh, T.H. Segmental duplications: an 'expanding' role in genomic instability and disease. Nat. Rev. Genet. 2, 791–800 (2001).

    Article  CAS  PubMed  Google Scholar 

  31. Zhang, X. et al. High-resolution mapping of genotype-phenotype relationships in cri du chat syndrome using array comparative genomic hybridization. Am. J. Hum. Genet. 76, 312–326 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Locke, D.P. et al. BAC microarray analysis of 15q11-q13 rearrangements and the impact of segmental duplications. J. Med. Genet. 41, 175–182 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Albertson, D.G. & Pinkel, D. Genomic microarrays in human genetic disease and cancer. Hum. Mol. Genet. 12 special issue 2, R145–R152 (2003).

    Article  CAS  PubMed  Google Scholar 

  34. Iafrate, A.J. et al. Detection of large-scale variation in the human genome. Nat. Genet. 36, 949–951 (2004).

    Article  CAS  PubMed  Google Scholar 

  35. Snijders, A.M. et al. Mapping segmental and sequence variations among laboratory mice using BAC array CGH. Genome Res. 15, 302–311 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Utermann, G. et al. Lp(a) glycoprotein phenotypes. Inheritance and relation to Lp(a)-lipoprotein concentrations in plasma. J. Clin. Invest. 80, 458–465 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. DeVries, S. et al. Array-based comparative genomic hybridization from formalin-fixed, paraffin-embedded breast tumors. J. Mol. Diagn. 7, 1–7 (2005).

    Article  Google Scholar 

  38. Snijders, A.M. et al. Rare amplicons implicate misspecification of cell fate in oral squamous cell carcinoma. Oncogene published online, 11 April 2005 (10.1038/sj.onc.1208601).

  39. Lage, J.M. et al. Whole genome analysis of genetic alterations in small DNA samples using hyperbranched strand displacement amplification and array-CGH. Genome Res. 13, 294–307 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Hosono, S. et al. Unbiased whole-genome amplification directly from clinical samples. Genome Res. 13, 954–964 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Daigo, Y. et al. Degenerate oligonucleotide primed-polymerase chain reaction-based array comparative genomic hybridization for extensive amplicon profiling of breast cancers: a new approach for the molecular analysis of paraffin-embedded cancer tissue. Am. J. Pathol. 158, 1623–1631 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Wang, G. et al. Balanced-PCR amplification allows unbiased identification of genomic copy changes in minute cell and tissue samples. Nucleic Acids Res. 32, e76 (2004).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Guillaud-Bataille, M. et al. Detecting single DNA copy number variations in complex genomes using one nanogram of starting DNA and BAC-array CGH. Nucleic Acids Res. 32, e112 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Tanabe, C. et al. Evaluation of a whole-genome amplification method based on adaptor-ligation PCR of randomly sheared genomic DNA. Genes Chromosomes Cancer 38, 168–176 (2003).

    Article  CAS  PubMed  Google Scholar 

  45. Liu, D. et al. LM-PCR permits highly representative whole genome amplification of DNA isolated from small number of cells and paraffin-embedded tumor tissue sections. Diagn. Mol. Pathol. 13, 105–115 (2004).

    Article  CAS  PubMed  Google Scholar 

  46. Wang, G. et al. DNA amplification method tolerant to sample degradation. Genome Res. 14, 2357–2366 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Fridlyand, J., Snijders, A.M., Pinkel, D., Albertson, D.G. & Jain, A.N. Hidden Markov models approach to the analysis of array CGH data. J. Multivariate Anal. 90, 132–153 (2004).

    Article  Google Scholar 

  48. Olshen, A.B., Venkatraman, E.S., Lucito, R. & Wigler, M. Circular binary segmentation for the analysis of array-based DNA copy number data. Biostatistics 5, 557–572 (2004).

    Article  PubMed  Google Scholar 

  49. Hupe, P., Stransky, N., Thiery, J.P., Radvanyi, F. & Barillot, E. Analysis of array CGH data: from signal ratio to gain and loss of DNA regions. Bioinformatics 20, 3413–3422 (2004).

    Article  CAS  PubMed  Google Scholar 

  50. Daruwala, R.S. et al. A versatile statistical analysis algorithm to detect genome copy number variation. Proc. Natl. Acad. Sci. USA 101, 16292–16297 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Wang, P., Kim, Y., Pollack, J., Narasimhan, B. & Tibshirani, R. A method for calling gains and losses in array CGH data. Biostatistics 6, 45–58 (2005).

    Article  PubMed  Google Scholar 

  52. Bocker, T., Ruschoff, J. & Fishel, R. Molecular diagnostics of cancer predisposition: hereditary non-polyposis colorectal carcinoma and mismatch repair defects. Biochim. Biophys. Acta 1423, O1–O10 (1999).

    CAS  PubMed  Google Scholar 

  53. Esteller, M. Epigenetic lesions causing genetic lesions in human cancer: promoter hypermethylation of DNA repair genes. Eur. J. Cancer 36, 2294–2300 (2000).

    Article  CAS  PubMed  Google Scholar 

  54. Snijders, A.M. et al. Shaping of tumor and drug-resistant genomes by instability and selection. Oncogene 22, 4370–4379 (2003).

    Article  CAS  PubMed  Google Scholar 

  55. O'Hagan, R.C. et al. Telomere dysfunction provokes regional amplification and deletion in cancer genomes. Cancer Cell 2, 149–155 (2002).

    Article  CAS  PubMed  Google Scholar 

  56. Waldman, F.M. et al. Chromosomal alterations in ductal carcinomas in situ and their in situ recurrences. J. Natl. Cancer Inst. 92, 313–320 (2000).

    Article  CAS  PubMed  Google Scholar 

  57. Albertson, D.G. Profiling breast cancer by array CGH. Breast Cancer Res. Treat. 78, 289–298 (2003).

    Article  CAS  PubMed  Google Scholar 

  58. Chin, K. et al. In situ analyses of genome instability in breast cancer. Nat. Genet. 36, 984–988 (2004).

    Article  CAS  PubMed  Google Scholar 

  59. Schwaenen, C. et al. Automated array-based genomic profiling in chronic lymphocytic leukemia: development of a clinical tool and discovery of recurrent genomic alterations. Proc. Natl. Acad. Sci. USA 101, 1039–1044 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Paris, P.L. et al. Whole genome scanning identifies genotypes associated with recurrence and metastasis in prostate tumors. Hum. Mol. Genet. 13, 1303–1313 (2004).

    Article  CAS  PubMed  Google Scholar 

  61. Callagy, G. et al. Identification and validation of prognostic markers in breast cancer with the complementary use of array-CGH and tissue microarrays. J. Pathol. 205, 388–396 (2005).

    Article  CAS  PubMed  Google Scholar 

  62. Weiss, M.M. et al. Genomic alterations in primary gastric adenocarcinomas correlate with clinicopathological characteristics and survival. Cell. Oncol. 26, 307–317 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Martinez-Climent, J.A. et al. Transformation of follicular lymphoma to diffuse large cell lymphoma is associated with a heterogeneous set of DNA copy number and gene expression alterations. Blood 101, 3109–3117 (2003).

    Article  CAS  PubMed  Google Scholar 

  64. Rubio-Moscardo, F. et al. Mantel cell lymphoma genotypes identified with CGH to BAC microarrays define a leukemic subgroup of disease and predict patient outcome. Blood published online 17 February 2005 (10.1182/blood-2004-10-3907).

    Google Scholar 

  65. Ioannidis, J.P., Ntzani, E.E., Trikalinos, T.A. & Contopoulos-Ioannidis, D.G. Replication validity of genetic association studies. Nat. Genet. 29, 306–309 (2001).

    Article  CAS  PubMed  Google Scholar 

  66. Freedman, M.L. et al. Assessing the impact of population stratification on genetic association studies. Nat. Genet. 36, 388–393 (2004).

    Article  CAS  PubMed  Google Scholar 

  67. Pollack, J.R. et al. Microarray analysis reveals a major direct role of DNA copy number alteration in the transcriptional program of human breast tumors. Proc. Natl. Acad. Sci. USA 99, 12963–12968 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Heidenblad, M. et al. Microarray analyses reveal strong influence of DNA copy number alterations on the transcriptional patterns in pancreatic cancer: implications for the interpretation of genomic amplifications. Oncogene 24, 1794–1801 (2005).

    Article  CAS  PubMed  Google Scholar 

  69. Hyman, E. et al. Impact of DNA amplification on gene expression patterns in breast cancer. Cancer Res. 62, 6240–6245 (2002).

    CAS  PubMed  Google Scholar 

  70. Press, M.F. et al. Evaluation of HER-2/neu gene amplification and overexpression: comparison of frequently used assay methods in a molecularly characterized cohort of breast cancer specimens. J. Clin. Oncol. 20, 3095–3105 (2002).

    Article  CAS  PubMed  Google Scholar 

  71. Maldonado, J.L. et al. Determinants of BRAF mutations in primary melanomas. J. Natl. Cancer Inst. 95, 1878–1890 (2003).

    Article  CAS  PubMed  Google Scholar 

  72. Ewart-Toland, A. et al. Identification of Stk6/STK15 as a candidate low-penetrance tumor-susceptibility gene in mouse and human. Nat. Genet. 34, 403–412 (2003).

    Article  CAS  PubMed  Google Scholar 

  73. Zardo, G. et al. Integrated genomic and epigenomic analyses pinpoint biallelic gene inactivation in tumors. Nat. Genet. 32, 453–458 (2002).

    Article  CAS  PubMed  Google Scholar 

  74. Cox, C. et al. A survey of homozygous deletions in human cancer genomes. Proc. Natl. Acad. Sci. USA 102, 4542–4547 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Huusko, P. et al. Nonsense-mediated decay microarray analysis identifies mutations of EPHB2 in human prostate cancer. Nat. Genet. 36, 979–983 (2004).

    Article  CAS  PubMed  Google Scholar 

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Pinkel, D., Albertson, D. Array comparative genomic hybridization and its applications in cancer. Nat Genet 37 (Suppl 6), S11–S17 (2005). https://doi.org/10.1038/ng1569

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