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[Cancer Research 65, 6071-6079, July 15, 2005]
© 2005 American Association for Cancer Research

Molecular Biology, Pathobiology, and Genetics

A Robust Algorithm for Copy Number Detection Using High-Density Oligonucleotide Single Nucleotide Polymorphism Genotyping Arrays

Yasuhito Nannya1, Masashi Sanada1, Kumi Nakazaki1, Noriko Hosoya1, Lili Wang1, Akira Hangaishi1, Mineo Kurokawa1, Shigeru Chiba1,2, Dione K. Bailey4, Giulia C. Kennedy4 and Seishi Ogawa1,3,5

1 Departments of Hematology/Oncology, 2 Cell Therapy/Transplantation Medicine, and 3 Regeneration Medicine for Hematopoiesis, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; 4 Affymetrix, Inc., Santa Clara, California; and 5 Core Research for Evolutional Science and Technology of Japan Science and Technology Corporation, Saitama, Japan

Requests for reprints: Seishi Ogawa, Department of Regeneration Medicine for Hematopoiesis, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Phone: 813-3815-5411, ext. 35609; Fax: 813-5804-6261; E-mail: sogawa-tky{at}umin.ac.jp.

We have developed a robust algorithm for copy number analysis of the human genome using high-density oligonucleotide microarrays containing 116,204 single-nucleotide polymorphisms. The advantages of this algorithm include the improvement of signal-to-noise (S/N) ratios and the use of an optimized reference. The raw S/N ratios were improved by accounting for the length and GC content of the PCR products using quadratic regressions. The use of constitutional DNA, when available, gives the lowest SD values (0.16 ± 0.03) and also enables allele-based copy number detection in cancer genomes, which can unmask otherwise concealed allelic imbalances. In the absence of constitutional DNA, optimized selection of multiple normal references with the highest S/N ratios, in combination with the data regressions, dramatically improves SD values from 0.67 ± 0.12 to 0.18 ± 0.03. These improvements allow for highly reliable comparison of data across different experimental conditions, detection of allele-based copy number changes, and more accurate estimations of the range and magnitude of copy number aberrations. This algorithm has been implemented in a software package called Copy Number Analyzer for Affymetrix GeneChip Mapping 100K arrays (CNAG). Overall, these enhancements make CNAG a useful tool for high-resolution detection of copy number alterations which can help in the understanding of the pathogenesis of cancers and other diseases as well as in exploring the complexities of the human genome.




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Nucleic Acids Res., March 27, 2007; (2007) gkm076v3.
[Abstract] [Full Text] [PDF]

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S. Jacobs, E. R. Thompson, Y. Nannya, G. Yamamoto, R. Pillai, S. Ogawa, D. K. Bailey, and I. G. Campbell
Genome-Wide, High-Resolution Detection of Copy Number, Loss of Heterozygosity, and Genotypes from Formalin-Fixed, Paraffin-Embedded Tumor Tissue Using Microarrays
Cancer Res., March 15, 2007; 67(6): 2544 - 2551.
[Abstract] [Full Text] [PDF]

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 DNA ResHome page
J. Y. Hehir-Kwa, M. Egmont-Petersen, I. M. Janssen, D. Smeets, A. G. van Kessel, and J. A. Veltman
Genome-wide Copy Number Profiling on High-density Bacterial Artificial Chromosomes, Single-nucleotide Polymorphisms, and Oligonucleotide Microarrays: A Platform Comparison based on Statistical Power Analysis
DNA Res, March 15, 2007; (2007) dsm002v1.
[Abstract] [Full Text] [PDF]

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 Genome ResHome page
J. Oosting, E. H. Lips, R. van Eijk, P. H.C. Eilers, K. Szuhai, C. Wijmenga, H. Morreau, and T. van Wezel
High-resolution copy number analysis of paraffin-embedded archival tissue using SNP BeadArrays
Genome Res., March 1, 2007; 17(3): 368 - 376.
[Abstract] [Full Text] [PDF]

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 Nucleic Acids ResHome page
L. Zhang, C. Wu, R. Carta, and H. Zhao
Free energy of DNA duplex formation on short oligonucleotide microarrays
Nucleic Acids Res., February 16, 2007; 35(3): e18 - e18.
[Abstract] [Full Text] [PDF]

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 Genome ResHome page
D. Komura, F. Shen, S. Ishikawa, K. R. Fitch, W. Chen, J. Zhang, G. Liu, S. Ihara, H. Nakamura, M. E. Hurles, et al.
Genome-wide detection of human copy number variations using high-density DNA oligonucleotide arrays
Genome Res., December 1, 2006; 16(12): 1575 - 1584.
[Abstract] [Full Text] [PDF]

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 Nucleic Acids ResHome page
P. Lamy, C. L. Andersen, F. P. Wikman, and C. Wiuf
Genotyping and annotation of Affymetrix SNP arrays
Nucleic Acids Res., September 1, 2006; 34(14): e100 - e100.
[Abstract] [Full Text] [PDF]

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 Genome ResHome page
D. A. Peiffer, J. M. Le, F. J. Steemers, W. Chang, T. Jenniges, F. Garcia, K. Haden, J. Li, C. A. Shaw, J. Belmont, et al.
High-resolution genomic profiling of chromosomal aberrations using Infinium whole-genome genotyping
Genome Res., September 1, 2006; 16(9): 1136 - 1148.
[Abstract] [Full Text] [PDF]

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 BloodHome page
B. A. Walker, P. E. Leone, M. W. Jenner, C. Li, D. Gonzalez, D. C. Johnson, F. M. Ross, F. E. Davies, and G. J. Morgan
Integration of global SNP-based mapping and expression arrays reveals key regions, mechanisms, and genes important in the pathogenesis of multiple myeloma
Blood, September 1, 2006; 108(5): 1733 - 1743.
[Abstract] [Full Text] [PDF]

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J. R. Downing and C. G. Mullighan
Tumor-Specific Genetic Lesions and Their Influence on Therapy in Pediatric Acute Lymphoblastic Leukemia
Hematology, January 1, 2006; 2006(1): 118 - 122.
[Abstract] [Full Text] [PDF]


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