Genomic organization and evolution of double minutes/homogeneously staining regions with MYC amplification in human cancer

Alberto L'Abbate, Gemma Macchia, Pietro D'Addabbo, Angelo Lonoce, Doron Tolomeo, Domenico Trombetta, Klaas Kok, Christoph Bartenhagen, Christopher W. Whelan, Orazio Palumbo, Marco Severgnini, Ingrid Cifola, Martin Dugas, Massimo Carella, Gianluca De Bellis, Mariano Rocchi, Lucia Carbone, Clelia Tiziana Storlazzi

Research output: Contribution to journalArticle

35 Scopus citations

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 nextgeneration sequencing, single nucleotide polymorphism array, fluorescent in situ hybridization and polymerase chain reaction-based techniques, we inferred the fine structure ofMYC-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 multistep 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.

Original languageEnglish (US)
Pages (from-to)9131-9145
Number of pages15
JournalNucleic acids research
Volume42
Issue number14
DOIs
StatePublished - 2014

ASJC Scopus subject areas

  • Genetics

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    L'Abbate, A., Macchia, G., D'Addabbo, P., Lonoce, A., Tolomeo, D., Trombetta, D., Kok, K., Bartenhagen, C., Whelan, C. W., Palumbo, O., Severgnini, M., Cifola, I., Dugas, M., Carella, M., De Bellis, G., Rocchi, M., Carbone, L., & Storlazzi, C. T. (2014). Genomic organization and evolution of double minutes/homogeneously staining regions with MYC amplification in human cancer. Nucleic acids research, 42(14), 9131-9145. https://doi.org/10.1093/nar/gku590