Allele-specific copy number analysis of tumor samples with aneuploidy and tumor heterogeneity

A characteristic feature of cancer cells is that their genomic DNA is altered [1]. Tumor cells frequently contain a wide range of aberrations, with gains, losses and translocations of genetic material often affecting a majority of the genome. In cancer, genomic aberrations are acquired during a process of tumor evolution, selecting for a tumor genome that provides growth and survival advantages over other cells.The SNP array is currently one of the most efficient technologies for detecting copy number aberrations in tumor cells. SNP arrays measure allele-specific signals from SNP probes (A and B), allowing detection of both copy number alterations and allelic imbalances. High-density SNP arrays are available primarily on Affymetrix and Illumina platforms. Both platforms were originally developed for genotyping of diploid genomes. In order to use them for copy number analysis of tumor genomes, specialized bioinformatic tools are required. The main aim of such tools is the identification of boundaries and copy number for every aberration.A commonly used strategy for identification of regions affected by genomic aberrations is segmentation of the total probe signals into genomic regions with similar average signal [2]. Conventional tools for copy number analysis only consider the total probe intensities relative to the average intensity of a set of (diploid) reference samples, usually called the Log-ratio [3]. Segments with an average Log-ratio near zero are often assumed to be copy number two, and any deviation beyond certain thresholds is called loss or gain accordingly.The allele-specific copy number - that is, the total copy number and the specific number of copies of each original sister chromosome - can be determined from the allele-specific signals of the SNP markers. Several methods detect relative differences in total signals and allele-specific signal without determining absolute copy number [4,5]. One tool provides a manual interpretation of Affymetrix 500 K