TY - JOUR T1 - sCNAphase: using haplotype resolved read depth to genotype somatic copy number alterations from low cellularity aneuploid tumors JF - bioRxiv DO - 10.1101/038828 SP - 038828 AU - Wenhan Chen AU - Alan J. Robertson AU - Devika Ganesamoorthy AU - Lachlan J.M. Coin Y1 - 2016/01/01 UR - http://biorxiv.org/content/early/2016/02/09/038828.abstract N2 - Accurate identification of copy number alterations is an essential step in understanding the events driving tumor progression. While a variety of algorithms have been developed to use high-throughput sequencing data to profile copy number changes, no tool is able to reliably characterize ploidy and genotype absolute copy number from tumors which contains less than 40% tumor DNA. To increase our power to resolve the copy number profile of these low cellularity tumor genomes, we developed a novel approach which pre-phases heterozygote germline SNPs in order to replace the commonly used ‘B-allele frequency’ with a more powerful ‘parental-haplotype frequency’. We also describe a novel ‘digital spectral karyotyping’ approach for visualization of copy number alterations.We apply our tool - sCNAphase - to characterize the copy number and loss-of-heterozygosity profiles of four publicly available breast cancer cell-lines. Comparisons to previous spectral karyotyping and microarray studies revealed that sCNAphase reliably identified overall ploidy and the individual copy number changes from each cell-line. Analysis of tumor-normal cell-line mixtures demonstrated the capacity of this method to determine the level of tumor purity as little as 5% tumor DNA and to consistently identify sCNAs and characterize ploidy in samples at 10% tumor purity. This novel methodology has the potential to bring sCNA profiling to low-cellularity tumors, a form of cancer unable to be profiled by current methods. ER -