title: Genomic organization and evolution of double minutes/homogeneously staining regions with MYC amplification in human cancer.
abstract: The mechanism for generating double minutes chromosomes (dmin) and homogeneously staining regions (hsr) in cancer is still poorly understood. Through an integrated approach combining next-generation sequencing, single nucleotide polymorphism array, fluorescent in situ hybridization and polymerase chain reaction-based techniques, we inferred the fine structure of MYC-containing dmin/hsr amplicons harboring sequences from several different chromosomes in seven tumor cell lines, and characterized an unprecedented number of hsr insertion sites. Local chromosome shattering involving a single-step catastrophic event (chromothripsis) was recently proposed to explain clustered chromosomal rearrangements and genomic amplifications in cancer. Our bioinformatics analyses based on the listed criteria to define chromothripsis led us to exclude it as the driving force underlying amplicon genesis in our samples. Instead, the finding of coexisting heterogeneous amplicons, differing in their complexity and chromosome content, in cell lines derived from the same tumor indicated the occurrence of a multi-step evolutionary process in the genesis of dmin/hsr. Our integrated approach allowed us to gather a complete view of the complex chromosome rearrangements occurring within MYC amplicons, suggesting that more than one model may be invoked to explain the origin of dmin/hsr in cancer. Finally, we identified PVT1 as a target of fusion events, confirming its role as breakpoint hotspot in MYC amplification.
authors.affiliation: Department of Biology, University of Bari, Bari, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: L'Abbate
authors.affiliation: Department of Biology, University of Bari, Bari, Italy.
authors.forename: Gemma
authors.initials: G
authors.lastname: Macchia
authors.affiliation: Department of Biology, University of Bari, Bari, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: D'Addabbo
authors.affiliation: Department of Biology, University of Bari, Bari, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Lonoce
authors.affiliation: Department of Biology, University of Bari, Bari, Italy.
authors.forename: Doron
authors.initials: D
authors.lastname: Tolomeo
authors.affiliation: Laboratory of Oncology, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Trombetta
authors.affiliation: Department of Genetics, University of Groningen, Groningen, The Netherlands.
authors.forename: Klaas
authors.initials: K
authors.lastname: Kok
authors.affiliation: Institute of Medical Informatics, University of Münster, Münster, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Bartenhagen
authors.affiliation: National Primate Research Center, Beaverton, Oregon, USA.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Whelan
authors.affiliation: Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy.
authors.forename: Orazio
authors.initials: O
authors.lastname: Palumbo
authors.affiliation: Institute for Biomedical Technologies, National Research Council, Milan, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Severgnini
authors.affiliation: Institute for Biomedical Technologies, National Research Council, Milan, Italy.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Cifola
authors.affiliation: Institute of Medical Informatics, University of Münster, Münster, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Dugas
authors.affiliation: Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Carella
authors.affiliation: Institute for Biomedical Technologies, National Research Council, Milan, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: De Bellis
authors.affiliation: Department of Biology, University of Bari, Bari, Italy.
authors.forename: Mariano
authors.initials: M
authors.lastname: Rocchi
authors.affiliation: National Primate Research Center, Beaverton, Oregon, USA.
authors.forename: Lucia
authors.initials: L
authors.lastname: Carbone
authors.affiliation: Department of Biology, University of Bari, Bari, Italy cleliatiziana.storlazzi@uniba.it.
authors.forename: Clelia Tiziana
authors.initials: CT
authors.lastname: Storlazzi
mesh_terms: D045744:Cell Line, Tumor; D002877:Chromosomes, Human / Q000737:chemistry*; D019143:Evolution, Molecular; D005784:Gene Amplification; D015870:Gene Expression; D050939:Gene Fusion; D052138:Genes, Neoplasm; D016259:Genes, myc; D015894:Genome, Human; D018922:HL-60 Cells; D006801:Humans; D009369:Neoplasms / Q000235:genetics*