title: Frequent occurrence of large duplications at reciprocal genomic rearrangement breakpoints in multiple myeloma and other tumors.
abstract: Using a combination of array comparative genomic hybridization, mate pair and cloned sequences, and FISH analyses, we have identified in multiple myeloma cell lines and tumors a novel and recurrent type of genomic rearrangement, i.e. interchromosomal rearrangements (translocations or insertions) and intrachromosomal inversions that contain long (1-4000 kb; median ∼100 kb) identical sequences adjacent to both reciprocal breakpoint junctions. These duplicated sequences were generated from sequences immediately adjacent to the breakpoint from at least one-but sometimes both-chromosomal donor site(s). Tandem duplications had a similar size distribution suggesting the possibility of a shared mechanism for generating duplicated sequences at breakpoints. Although about 25% of apparent secondary rearrangements contained these duplications, primary IGH translocations rarely, if ever, had large duplications at breakpoint junctions. Significantly, these duplications often contain super-enhancers and/or oncogenes (e.g. MYC) that are dysregulated by rearrangements during tumor progression. We also found that long identical sequences often were identified at both reciprocal breakpoint junctions in six of eight other tumor types. Finally, we have been unable to find reports of similar kinds of rearrangements in wild-type or mutant prokaryotes or lower eukaryotes such as yeast.
authors.affiliation: Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-4265, USA.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Demchenko
authors.affiliation: Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-4265, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Roschke
authors.affiliation: Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-4265, USA.
authors.forename: Wei-Dong
authors.initials: WD
authors.lastname: Chen
authors.affiliation: Division of Biomedical Statistics and Informatics, Mayo Clinic, 4500 San Pablo Road South, Jacksonville, FL 32224, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Asmann
authors.affiliation: Comprehensive Cancer Center, Mayo Clinic Arizona, 13400 E. Shea Boulevard, Scottsdale, AZ 85259, USA.
authors.forename: Peter Leif
authors.initials: PL
authors.lastname: Bergsagel
authors.affiliation: Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-4265, USA kuehlw@helix.nih.gov.
authors.forename: Walter Michael
authors.initials: WM
authors.lastname: Kuehl
mesh_terms: D001483:Base Sequence; D019457:Chromosome Breakage; D007446:Chromosome Inversion; D018628:Gene Dosage; D020440:Gene Duplication; D015321:Gene Rearrangement; D020131:Genes, Duplicate; D056426:Genetic Loci; D015894:Genome, Human; D006801:Humans; D008957:Models, Genetic; D009101:Multiple Myeloma / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism
chemical_list: D016271:Proto-Oncogene Proteins c-myc