title: sCNAphase: using haplotype resolved read depth to genotype somatic copy number alterations from low cellularity aneuploid tumors.
abstract: 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 tumor samples that contain less than 40% tumor cells. To increase our power to resolve the copy number profile from low-cellularity tumor samples, we developed a novel approach that pre-phases heterozygote germline single nucleotide polymorphisms (SNPs) in order to replace the commonly used 'B-allele frequency' with a more powerful 'parental-haplotype frequency'. 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 as well as the individual copy number mutations from each cell-line. Analysis of artificial cell-line mixtures demonstrated the capacity of this method to determine the level of tumor cellularity, consistently identify sCNAs and characterize ploidy in samples with as little as 10% tumor cells. This novel methodology has the potential to bring sCNA profiling to low-cellularity tumors, a form of cancer unable to be accurately studied by current methods.
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland, 4072, Australia.
authors.forename: Wenhan
authors.initials: W
authors.lastname: Chen
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland, 4072, Australia.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Robertson
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland, 4072, Australia.
authors.forename: Devika
authors.initials: D
authors.lastname: Ganesamoorthy
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland, 4072, Australia.
authors.forename: Lachlan J M
authors.initials: LJM
authors.lastname: Coin
mesh_terms: D000465:Algorithms; D000782:Aneuploidy; D002452:Cell Count; D045744:Cell Line, Tumor; D056915:DNA Copy Number Variations; D018628:Gene Dosage; D006239:Haplotypes; D006579:Heterozygote; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D017422:Sequence Analysis, DNA; D012984:Software