SCDT: Detecting somatic CNVs of low chimeric ratio in cf-DNA

Abstract Motivation Sequencing of cell-free DNA (cf-DNA) has enabled Noninvasive Prenatal Testing (NIPT) and”liquid biopsy” of cancers. However, while the aneuploidy and point mutations were focused on by most of NITP and liquid biopsy studies, detecting sub-chromosome CNVs that affect a few to dozens of megabases was rarely reported, likely attributable to the difficulty in accurately identifying them, especially for those present in a small fraction of cf-DNA. Results We developed a somatic CNV detection tool (SCDT), for detecting sub-chromosome CNVs in cf-DNA using whole genome sequencing (WGS) data or off-target reads in target sequencing data. Additional to using control samples for correcting genome position specific bias, two GC correction steps were performed, which regressed GC content of DNA fragments and that of genome bins, respectively. After GC correction, the coefficients of variation of copy ratios approximated the lower boundary of theoretical values, suggesting removing of almost all systematic errors. Finally, CNVs were detected by a piecewise least squares fitting based segmentation algorithm, which outperformed other segmentation methods. We applied SCDT on simulated and real maternal plasma samples, and target cf-DNA sequencing of 118 normal individuals and 240 cancer patients, and demonstrated high sensitivity and specificity. Availability SCDT is available at https://github.com/Martiantian/Somatic_cnv_detect_tool. Contact zhuhongmei@genomics.cn Supplementary Information Supplementary data are available at Bioinformatics online