A sequence-level map of chromosomal breakpoints in the MCF-7 breast cancer cell line yields insights into the evolution of a cancer genome.

TitleA sequence-level map of chromosomal breakpoints in the MCF-7 breast cancer cell line yields insights into the evolution of a cancer genome.
Publication TypeJournal Article
Year of Publication2009
AuthorsHampton, OA, Hollander, PDen, Miller, CA, Delgado, DA, Li, J, Coarfa, C, Harris, RA, Richards, S, Scherer, SE, Muzny, DM, Gibbs, RA, Lee, AV, Milosavljevic, A
JournalGenome Res
Date Published2009 Feb
KeywordsBreast Neoplasms, Cell Line, Tumor, Chromosome Breakage, Chromosome Mapping, Chromosomes, Artificial, Bacterial, DNA Repair, Evolution, Molecular, Gene Expression Profiling, Genes, Neoplasm, Genome, Human, Humans, Locus Control Region, Models, Biological, Mutant Chimeric Proteins, Sequence Analysis, DNA

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.

Alternate JournalGenome Res
PubMed ID19056696
PubMed Central IDPMC2652200
Grant ListR01 HG002583 / HG / NHGRI NIH HHS / United States
R33 CA114151 / CA / NCI NIH HHS / United States
R21 CA128496 / CA / NCI NIH HHS / United States
1 R01 HG02583 / HG / NHGRI NIH HHS / United States

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