title: RefCNV: Identification of Gene-Based Copy Number Variants Using Whole Exome Sequencing.
abstract: With rapid advances in DNA sequencing technologies, whole exome sequencing (WES) has become a popular approach for detecting somatic mutations in oncology studies. The initial intent of WES was to characterize single nucleotide variants, but it was observed that the number of sequencing reads that mapped to a genomic region correlated with the DNA copy number variants (CNVs). We propose a method RefCNV that uses a reference set to estimate the distribution of the coverage for each exon. The construction of the reference set includes an evaluation of the sources of variability in the coverage distribution. We observed that the processing steps had an impact on the coverage distribution. For each exon, we compared the observed coverage with the expected normal coverage. Thresholds for determining CNVs were selected to control the false-positive error rate. RefCNV prediction correlated significantly (r = 0.96-0.86) with CNV measured by digital polymerase chain reaction for MET (7q31), EGFR (7p12), or ERBB2 (17q12) in 13 tumor cell lines. The genome-wide CNV analysis showed a good overall correlation (Spearman's coefficient = 0.82) between RefCNV estimation and publicly available CNV data in Cancer Cell Line Encyclopedia. RefCNV also showed better performance than three other CNV estimation methods in genome-wide CNV analysis.
authors.affiliation: Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Lun-Ching
authors.initials: LC
authors.lastname: Chang
authors.affiliation: Molecular Characterization and Clinical Assay Development Laboratory, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
authors.forename: Biswajit
authors.initials: B
authors.lastname: Das
authors.affiliation: Molecular Characterization and Clinical Assay Development Laboratory, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
authors.forename: Chih-Jian
authors.initials: CJ
authors.lastname: Lih
authors.affiliation: Molecular Characterization and Clinical Assay Development Laboratory, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
authors.forename: Han
authors.initials: H
authors.lastname: Si
authors.affiliation: Molecular Characterization and Clinical Assay Development Laboratory, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
authors.forename: Corinne E
authors.initials: CE
authors.lastname: Camalier
authors.affiliation: Molecular Characterization and Clinical Assay Development Laboratory, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
authors.forename: Paul M
authors.initials: PM
authors.lastname: McGregor
authors.affiliation: Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Polley
keywords: copy number variation; methodology; next-generation sequencing; whole exome sequencing