title: Ring chromosomes, breakpoint clusters, and neocentromeres in sarcomas.
abstract: Gene amplification is relatively common in tumors. In certain subtypes of sarcoma, it often occurs in the form of ring and/or giant rod-shaped marker (RGM) chromosomes whose mitotic stability is frequently rescued by ectopic novel centromeres (neocentromeres). Little is known about the origin and structure of these RGM chromosomes, including how they arise, their internal organization, and which sequences underlie the neocentromeres. To address these questions, 42 sarcomas with RGM chromosomes were investigated to detect regions prone to double strand breaks and possible functional or structural constraints driving the amplification process. We found nine breakpoint cluster regions potentially involved in the genesis of RGM chromosomes, which turned out to be significantly enriched in poly-pyrimidine traits. Some of the clusters were located close to genes already known to be relevant for sarcomas, thus indicating a potential functional constraint, while others mapped to transcriptionally inactive chromatin domains enriched in heterochromatic sites. Of note, five neocentromeres were identified after analyzing 13 of the cases by fluorescent in situ hybridization. ChIP-on-chip analysis with antibodies against the centromeric protein CENP-A showed that they were a patchwork of small genomic segments derived from different chromosomes, likely joint to form a contiguous sequence during the amplification process.
authors.affiliation: Department of Biology, University of Bari, Bari, Italy; Department of Clinical Genetics, University and Regional Laboratories, Lund University, Lund, Sweden.
authors.forename: Gemma
authors.initials: G
authors.lastname: Macchia
authors.forename: Karolin H
authors.initials: KH
authors.lastname: Nord
authors.forename: Monica
authors.initials: M
authors.lastname: Zoli
authors.forename: Stefania
authors.initials: S
authors.lastname: Purgato
authors.forename: Pietro
authors.initials: P
authors.lastname: D'Addabbo
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Whelan
authors.forename: Lucia
authors.initials: L
authors.lastname: Carbone
authors.forename: Giovanni
authors.initials: G
authors.lastname: Perini
authors.forename: Fredrik
authors.initials: F
authors.lastname: Mertens
authors.forename: Mariano
authors.initials: M
authors.lastname: Rocchi
authors.forename: Clelia Tiziana
authors.initials: CT
authors.lastname: Storlazzi
mesh_terms: D002503:Centromere / Q000235:genetics; D056905:Chromosome Breakpoints; D044127:Epigenesis, Genetic; D005784:Gene Amplification / Q000235:genetics; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D012303:Ring Chromosomes; D012509:Sarcoma / Q000235:genetics* / Q000648:ultrastructure