Comprehensive analysis of structural variants in breast cancer genomes using single-molecule sequencing.

TitleComprehensive analysis of structural variants in breast cancer genomes using single-molecule sequencing.
Publication TypeJournal Article
Year of Publication2020
AuthorsAganezov, S, Goodwin, S, Sherman, RM, Sedlazeck, FJ, Arun, G, Bhatia, S, Lee, I, Kirsche, M, Wappel, R, Kramer, M, Kostroff, K, Spector, DL, Timp, W, W McCombie, R, Schatz, MC
JournalGenome Res
Date Published2020 Sep
KeywordsBreast Neoplasms, Cell Line, Tumor, DNA Copy Number Variations, DNA Methylation, DNA, Neoplasm, Female, Genomic Structural Variation, Humans, Nanopores, Organoids, RNA-Seq, Whole Genome Sequencing

Improved identification of structural variants (SVs) in cancer can lead to more targeted and effective treatment options as well as advance our basic understanding of the disease and its progression. We performed whole-genome sequencing of the SKBR3 breast cancer cell line and patient-derived tumor and normal organoids from two breast cancer patients using Illumina/10x Genomics, Pacific Biosciences (PacBio), and Oxford Nanopore Technologies (ONT) sequencing. We then inferred SVs and large-scale allele-specific copy number variants (CNVs) using an ensemble of methods. Our findings show that long-read sequencing allows for substantially more accurate and sensitive SV detection, with between 90% and 95% of variants supported by each long-read technology also supported by the other. We also report high accuracy for long reads even at relatively low coverage (25×-30×). Furthermore, we integrated SV and CNV data into a unifying karyotype-graph structure to present a more accurate representation of the mutated cancer genomes. We find hundreds of variants within known cancer-related genes detectable only through long-read sequencing. These findings highlight the need for long-read sequencing of cancer genomes for the precise analysis of their genetic instability.

Alternate JournalGenome Res
PubMed ID32887686
PubMed Central IDPMC7545150
Grant ListR01 HG006677 / HG / NHGRI NIH HHS / United States
T32 GM007057 / GM / NIGMS NIH HHS / United States
R50 CA243890 / CA / NCI NIH HHS / United States
R21 CA220411 / CA / NCI NIH HHS / United States
P30 CA045508 / CA / NCI NIH HHS / United States
R01 HG009190 / HG / NHGRI NIH HHS / United States

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