Abstract 45: Accurate total and allele-specific copy number measurements in mosaic tumors

Abstract

Abstract For the characterization of genomic copy number changes that occur in the development and progression of cancer, oligonucleotide array comparative genomic hybridization (aCGH) offers high-resolution and precise determination of chromosomal copy number and genome-wide aberrations. We recently reported a new method for making simultaneous measurements of single nucleotide polymorphisms (SNPs) and copy number alterations in the same microarray assay. The combined assay can detect copy-number neutral events, such as acquired loss of heterozygosity (LOH), as well as allelic imbalance in and around amplified regions. Previously reported algorithms for analyzing Agilent CGH+SNP data were able to genotype primarily diploid samples and to detect regions of constitutional LOH. However, tumor heterogeneity, aneuploidy and variable sample quality create significant challenges for both solid and liquid tumors. Our earlier methods were often unable to cope with the high levels of aneuploidy sometimes found in solid tumors, or with admixtures of normal cells and aberrant cells. We now describe new computational methods which can determine total copy number, aneuploid fraction, and allele-specific copy number in many aneuploid tumor samples, even when mixed with up to 80% normal tissue. We report results from genomic DNA isolated from a cancer cell line, a blood sample, and a solid tumor. Each of these sample types presents novel challenges. The cell line we studied, though largely monoclonal, is highly aneuploid. The blood DNA is of high quality, but the fraction of tumor cells in the sample is low. The solid tumor DNA is of relatively low quality, and composed of multiple aberrant clones. We were able to determine the aneuploid fraction of the tumors, and to measure copy number variation in samples with as little as 20% tumor cell content. In addition to detecting copy-neutral LOH regions, we also measured allele-specific copy number, both of the aberrant clone and of admixed normal cells. The new analysis methods allow the extension of the extra allelic information available from the CGH+SNP assay to cancer samples. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 45. doi:10.1158/1538-7445.AM2011-45