title: Single-molecule analysis reveals widespread structural variation in multiple myeloma.
abstract: Multiple myeloma (MM), a malignancy of plasma cells, is characterized by widespread genomic heterogeneity and, consequently, differences in disease progression and drug response. Although recent large-scale sequencing studies have greatly improved our understanding of MM genomes, our knowledge about genomic structural variation in MM is attenuated due to the limitations of commonly used sequencing approaches. In this study, we present the application of optical mapping, a single-molecule, whole-genome analysis system, to discover new structural variants in a primary MM genome. Through our analysis, we have identified and characterized widespread structural variation in this tumor genome. Additionally, we describe our efforts toward comprehensive characterization of genome structure and variation by integrating our findings from optical mapping with those from DNA sequencing-based genomic analysis. Finally, by studying this MM genome at two time points during tumor progression, we have demonstrated an increase in mutational burden with tumor progression at all length scales of variation.
authors.affiliation: Biophysics Graduate Program, University of Wisconsin-Madison, Madison, WI 53706; Laboratory for Molecular and Computational Genomics, Department of Chemistry, Laboratory of Genetics and Biotechnology Center, University of Wisconsin-Madison, Madison, WI 53706; University of Wisconsin Carbone Cancer Center, Madison, WI 53705;
authors.forename: Aditya
authors.initials: A
authors.lastname: Gupta
authors.affiliation: Laboratory for Molecular and Computational Genomics, Department of Chemistry, Laboratory of Genetics and Biotechnology Center, University of Wisconsin-Madison, Madison, WI 53706; University of Wisconsin Carbone Cancer Center, Madison, WI 53705;
authors.forename: Michael
authors.initials: M
authors.lastname: Place
authors.affiliation: Laboratory for Molecular and Computational Genomics, Department of Chemistry, Laboratory of Genetics and Biotechnology Center, University of Wisconsin-Madison, Madison, WI 53706; University of Wisconsin Carbone Cancer Center, Madison, WI 53705;
authors.forename: Steven
authors.initials: S
authors.lastname: Goldstein
authors.affiliation: Indian Statistical Institute, New Delhi 110016, India;
authors.forename: Deepayan
authors.identifier: http://orcid.org/0000-0003-4107-1553
authors.initials: D
authors.lastname: Sarkar
authors.affiliation: Laboratory for Molecular and Computational Genomics, Department of Chemistry, Laboratory of Genetics and Biotechnology Center, University of Wisconsin-Madison, Madison, WI 53706; University of Wisconsin Carbone Cancer Center, Madison, WI 53705;
authors.forename: Shiguo
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Laboratory for Molecular and Computational Genomics, Department of Chemistry, Laboratory of Genetics and Biotechnology Center, University of Wisconsin-Madison, Madison, WI 53706; University of Wisconsin Carbone Cancer Center, Madison, WI 53705;
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Potamousis
authors.affiliation: University of Wisconsin Carbone Cancer Center, Madison, WI 53705; Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705;
authors.forename: Jaehyup
authors.initials: J
authors.lastname: Kim
authors.affiliation: University of Wisconsin Carbone Cancer Center, Madison, WI 53705; Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705;
authors.forename: Claire
authors.initials: C
authors.lastname: Flanagan
authors.affiliation: Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801;
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: University of Wisconsin Carbone Cancer Center, Madison, WI 53705; Department of Statistics, University of Wisconsin-Madison, Madison, WI 53706;
authors.forename: Michael A
authors.initials: MA
authors.lastname: Newton
authors.affiliation: University of Wisconsin Carbone Cancer Center, Madison, WI 53705; Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705;
authors.forename: Natalie S
authors.initials: NS
authors.lastname: Callander
authors.affiliation: University of Wisconsin Carbone Cancer Center, Madison, WI 53705; Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705;
authors.forename: Peiman
authors.initials: P
authors.lastname: Hematti
authors.affiliation: University of Wisconsin Carbone Cancer Center, Madison, WI 53705; Department of Cell and Regenerative Biology, University of Wisconsin-Madison Blood Research Program, Madison, WI 53705.
authors.forename: Emery H
authors.initials: EH
authors.lastname: Bresnick
authors.affiliation: Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801;
authors.forename: Jian
authors.initials: J
authors.lastname: Ma
authors.affiliation: University of Wisconsin Carbone Cancer Center, Madison, WI 53705; Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705;
authors.forename: Fotis
authors.initials: F
authors.lastname: Asimakopoulos
authors.affiliation: Biophysics Graduate Program, University of Wisconsin-Madison, Madison, WI 53706; Laboratory for Molecular and Computational Genomics, Department of Chemistry, Laboratory of Genetics and Biotechnology Center, University of Wisconsin-Madison, Madison, WI 53706; University of Wisconsin Carbone Cancer Center, Madison, WI 53705; dcschwartz@wisc.edu.
authors.forename: David C
authors.initials: DC
authors.lastname: Schwartz
mesh_terms: D004247:DNA / Q000235:genetics; D056915:DNA Copy Number Variations; D006801:Humans; D019656:Loss of Heterozygosity; D009101:Multiple Myeloma / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide
chemical_list: D004247:DNA
keywords: DNA sequencing; copy number; multiple myeloma; optical mapping; structural variation