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

Aganezov, S., Goodwin, S., Sherman, R. M., Sedlazeck, F. J., Arun, G., Bhatia, S., Lee, I., Kirsche, M., Wappel, R., Kramer, M., Kostroff, K., Spector, D. L., Timp, W., McCombie, W. R., Schatz, M. C. (September 2020) Comprehensive analysis of structural variants in breast cancer genomes using single-molecule sequencing. Genome Res, 30 (9). pp. 1258-1273. ISSN 1088-9051 (Print)1088-9051

DOI: 10.1101/gr.260497.119


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.

Item Type: Paper
Additional Information: 1549-5469 Aganezov, Sergey Goodwin, Sara Sherman, Rachel M Sedlazeck, Fritz J Orcid: 0000-0001-6040-2691 Arun, Gayatri Bhatia, Sonam Lee, Isac Kirsche, Melanie Wappel, Robert Kramer, Melissa Kostroff, Karen Spector, David L Timp, Winston Orcid: 0000-0003-2083-6027 McCombie, W Richard Schatz, Michael C P30 CA045508/CA/NCI NIH HHS/United States R01 HG006677/HG/NHGRI NIH HHS/United States R01 HG009190/HG/NHGRI NIH HHS/United States R21 CA220411/CA/NCI NIH HHS/United States Journal Article Genome Res. 2020 Sep;30(9):1258-1273. doi: 10.1101/gr.260497.119. Epub 2020 Sep 4.
Subjects: diseases & disorders > cancer > cancer types > breast cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > genomes
structural biology
CSHL Authors:
Communities: CSHL labs > McCombie lab
CSHL labs > Schatz lab
CSHL labs > Spector lab
CSHL Cancer Center Program > Cancer Genetics and Genomics Program
CSHL Cancer Center Program > Gene Regulation and Inheritance Program
Depositing User: Matthew Dunn
Date: September 2020
Date Deposited: 20 Apr 2021 02:27
Last Modified: 08 Jun 2021 13:18
PMCID: PMC7545150
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