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.
Highlights
Somatic copy number alterations represent an important class of mutation in the cancer genome, evident by the large number of short focal sCNAs and larger chromosomal scale changes seen in the analysis of individual tumor genomes [1]
We evaluated the performance of sCNAphase against two state-of-the-art algorithms (CLImAT and ASCAT) using mixture samples derived from whole genome sequence data from 4 well-characterized tumor cell-line samples covering a range of ploidies with known copy number information from single nucleotide polymorphisms (SNPs) array and Spectral karyotyping (SKY) data
Haplotype phasing greatly improves the power to identify sCNA from allelic depth The Ballele frequency (BAF) is commonly used to detect the presence of copy number variants (CNVs) in normal, diploid genome [33]
Summary
Somatic copy number alterations (sCNAs) represent an important class of mutation in the cancer genome, evident by the large number of short focal sCNAs and larger chromosomal scale changes seen in the analysis of individual tumor genomes [1]. This class of mutation has been linked to tumor progression, metastasis, multidrug resistance and poor clinical outcomes [2,3,4,5,6]. As a result, determining the sCNAs in an individual tumor sample has become standard practice in pathology labs for the treatment of some cancers. This type of analysis is routinely used to assign the optimal chemotherapeutic treatments for patients with breast cancer who contain additional copies of the HER2 gene [11,12]
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