TY - JOUR
T1 - Ring chromosomes, breakpoint clusters, and neocentromeres in sarcomas
AU - Macchia, Gemma
AU - Nord, Karolin H.
AU - Zoli, Monica
AU - Purgato, Stefania
AU - D'Addabbo, Pietro
AU - Whelan, Christopher W.
AU - Carbone, Lucia
AU - Perini, Giovanni
AU - Mertens, Fredrik
AU - Rocchi, Mariano
AU - Storlazzi, Clelia Tiziana
N1 - Publisher Copyright:
© 2014 Wiley Periodicals, Inc.
PY - 2015/3/1
Y1 - 2015/3/1
N2 - 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.
AB - 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.
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U2 - 10.1002/gcc.22228
DO - 10.1002/gcc.22228
M3 - Article
C2 - 25421174
AN - SCOPUS:84921464511
SN - 1045-2257
VL - 54
SP - 156
EP - 167
JO - Genes Chromosomes and Cancer
JF - Genes Chromosomes and Cancer
IS - 3
ER -