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. 2010 Jan;11(1):164-75.
doi: 10.1093/biostatistics/kxp045. Epub 2009 Oct 15.

PICNIC: an algorithm to predict absolute allelic copy number variation with microarray cancer data

Chris D Greenman  1 , Graham Bignell, Adam Butler, Sarah Edkins, Jon Hinton, Dave Beare, Sajani Swamy, Thomas Santarius, Lina Chen, Sara Widaa, P Andy Futreal, Michael R Stratton
Affiliations

PICNIC: an algorithm to predict absolute allelic copy number variation with microarray cancer data

Chris D Greenman et al. Biostatistics. 2010 Jan.

Abstract

High-throughput oligonucleotide microarrays are commonly employed to investigate genetic disease, including cancer. The algorithms employed to extract genotypes and copy number variation function optimally for diploid genomes usually associated with inherited disease. However, cancer genomes are aneuploid in nature leading to systematic errors when using these techniques. We introduce a preprocessing transformation and hidden Markov model algorithm bespoke to cancer. This produces genotype classification, specification of regions of loss of heterozygosity, and absolute allelic copy number segmentation. Accurate prediction is demonstrated with a combination of independent experimental techniques. These methods are exemplified with affymetrix genome-wide SNP6.0 data from 755 cancer cell lines, enabling inference upon a number of features of biological interest. These data and the coded algorithm are freely available for download.

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Figures

Fig. 1.
Fig. 1.
Allelic intensities for a single SNP across multiple samples. (A) The A allele intensity is plotted against the B allele intensity for each wild-type training sample at a single polymorphic probe. The MAP estimates of the linearly separated mean allelic intensities for genotypes AA, AB, and BB are indicated in red. (B) The same allelic intensities are plotted using the cancer samples. The significant reduction in clustering is evident.
Fig. 2.
Fig. 2.
Genome-wide copy number estimates of diploid, triploid, and quadraploid samples HCC1806, HCC1187, and ZR-75-30, respectively. Copy number estimates are obtained using SKY (dashed), Birdsuite (red), and PICNIC (green).
Fig. 3.
Fig. 3.
Absolute copy number, genotype intensity, and break-point likelihoods for cancer cell lines HCC1187. Each plot contains 3 sections. First are copy number intensities, followed by genotype intensities. Associated genotypes are indicated. Green and blue lines indicate total and minor estimated copy number. Black and red lines represent heterozygous and homozygous segments. Finally, the likelihoods of state change are plotted. The horizontal scale is genomic position in megabases. Vertical scales represent chromosomal copy number. (A and B) derive from chromosomes 14 and 19, respectively.
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