title: Long-range massively parallel mate pair sequencing detects distinct mutations and similar patterns of structural mutability in two breast cancer cell lines.
abstract: Cancer genomes frequently undergo genomic instability resulting in accumulation of chromosomal rearrangement. To date, one of the main challenges has been to confidently and accurately identify these rearrangements by using short-read massively parallel sequencing. We were able to improve cancer rearrangement detection by combining two distinct massively parallel sequencing strategies: fosmid-sized (36 kb on average) and standard 5 kb mate pair libraries. We applied this combined strategy to map rearrangements in two breast cancer cell lines, MCF7 and HCC1954. We detected and validated a total of 91 somatic rearrangements in MCF7 and 25 in HCC1954, including genomic alterations corresponding to previously reported transcript aberrations in these two cell lines. Each of the genomes contains two types of breakpoints: clustered and dispersed. In both cell lines, the dispersed breakpoints show enrichment for low copy repeats, while the clustered breakpoints associate with high copy number amplifications. Comparing the two genomes, we observed highly similar structural mutational spectra affecting different sets of genes, pointing to similar histories of genomic instability against the background of very different gene network perturbations.
authors.affiliation: Graduate Program in Structural and Computational Biology and Molecular Biophysics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. ohampton@bionanomatrix.com
authors.forename: Oliver A
authors.initials: OA
authors.lastname: Hampton
authors.forename: Maxim
authors.initials: M
authors.lastname: Koriabine
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Miller
authors.forename: Cristian
authors.initials: C
authors.lastname: Coarfa
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.forename: Petra
authors.initials: P
authors.lastname: Den Hollander
authors.forename: Caroline
authors.initials: C
authors.lastname: Schoenherr
authors.forename: Lucia
authors.initials: L
authors.lastname: Carbone
authors.forename: Mikhail
authors.initials: M
authors.lastname: Nefedov
authors.forename: Boudewijn F H
authors.initials: BF
authors.lastname: Ten Hallers
authors.forename: Adrian V
authors.initials: AV
authors.lastname: Lee
authors.forename: Pieter J
authors.initials: PJ
authors.lastname: De Jong
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Milosavljevic
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics*; D045744:Cell Line, Tumor; D002869:Chromosome Aberrations; D002874:Chromosome Mapping; D004273:DNA, Neoplasm / Q000032:analysis / Q000235:genetics; D005260:Female; D015894:Genome, Human; D042822:Genomic Instability; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D009154:Mutation / Q000235:genetics*; D016133:Polymerase Chain Reaction; D017422:Sequence Analysis, DNA
chemical_list: D004273:DNA, Neoplasm