title: A sequence-level map of chromosomal breakpoints in the MCF-7 breast cancer cell line yields insights into the evolution of a cancer genome.
abstract: By applying a method that combines end-sequence profiling and massively parallel sequencing, we obtained a sequence-level map of chromosomal aberrations in the genome of the MCF-7 breast cancer cell line. A total of 157 distinct somatic breakpoints of two distinct types, dispersed and clustered, were identified. A total of 89 breakpoints are evenly dispersed across the genome. A majority of dispersed breakpoints are in regions of low copy repeats (LCRs), indicating a possible role for LCRs in chromosome breakage. The remaining 68 breakpoints form four distinct clusters of closely spaced breakpoints that coincide with the four highly amplified regions in MCF-7 detected by array CGH located in the 1p13.1-p21.1, 3p14.1-p14.2, 17q22-q24.3, and 20q12-q13.33 chromosomal cytobands. The clustered breakpoints are not significantly associated with LCRs. Sequences flanking most (95%) breakpoint junctions are consistent with double-stranded DNA break repair by nonhomologous end-joining or template switching. A total of 79 known or predicted genes are involved in rearrangement events, including 10 fusions of coding exons from different genes and 77 other rearrangements. Four fusions result in novel expressed chimeric mRNA transcripts. One of the four expressed fusion products (RAD51C-ATXN7) and one gene truncation (BRIP1 or BACH1) involve genes coding for members of protein complexes responsible for homology-driven repair of double-stranded DNA breaks. Another one of the four expressed fusion products (ARFGEF2-SULF2) involves SULF2, a regulator of cell growth and angiogenesis. We show that knock-down of SULF2 in cell lines causes tumorigenic phenotypes, including increased proliferation, enhanced survival, and increased anchorage-independent growth.
authors.affiliation: Bioinformatics Research Laboratory, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Oliver A
authors.initials: OA
authors.lastname: Hampton
authors.forename: Petra
authors.initials: P
authors.lastname: Den Hollander
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Miller
authors.forename: David A
authors.initials: DA
authors.lastname: Delgado
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.forename: Cristian
authors.initials: C
authors.lastname: Coarfa
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Harris
authors.forename: Stephen
authors.initials: S
authors.lastname: Richards
authors.forename: Steven E
authors.initials: SE
authors.lastname: Scherer
authors.forename: Donna M
authors.initials: DM
authors.lastname: Muzny
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.forename: Adrian V
authors.initials: AV
authors.lastname: Lee
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Milosavljevic
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D019457:Chromosome Breakage; D002874:Chromosome Mapping / Q000379:methods; D022202:Chromosomes, Artificial, Bacterial / Q000737:chemistry / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D019143:Evolution, Molecular; D020869:Gene Expression Profiling; D052138:Genes, Neoplasm; D015894:Genome, Human; D006801:Humans; D019901:Locus Control Region / Q000235:genetics; D008954:Models, Biological; D050506:Mutant Chimeric Proteins / Q000235:genetics; D017422:Sequence Analysis, DNA / Q000379:methods
chemical_list: D050506:Mutant Chimeric Proteins