Gene amplification as double minutes or homogeneously staining regions in solid tumors: Origin and structure
- Clelia Tiziana Storlazzi1,
- Angelo Lonoce1,
- Maria C. Guastadisegni1,
- Domenico Trombetta1,
- Pietro D'Addabbo1,
- Giulia Daniele1,
- Alberto L'Abbate1,
- Gemma Macchia1,
- Cecilia Surace1,7,
- Klaas Kok2,
- Reinhard Ullmann3,
- Stefania Purgato4,
- Orazio Palumbo5,
- Massimo Carella5,
- Peter F. Ambros6 and
- Mariano Rocchi1,8
- 1 Department of Genetics and Microbiology, University of Bari, Bari 70126, Italy;
- 2 Department of Genetics, University Medical Centre Groningen, University of Groningen, Groningen 9700 RR, The Netherlands;
- 3 Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Berlin 14195, Germany;
- 4 Department of Biology, University of Bologna, Bologna 40126, Italy;
- 5 Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo (FG) 71013, Italy;
- 6 Children's Cancer Research Institute (CCRI), St. Anna Kinderkrebsforschung, Vienna A-1090, Austria
Abstract
Double minutes (dmin) and homogeneously staining regions (hsr) are the cytogenetic hallmarks of genomic amplification in cancer. Different mechanisms have been proposed to explain their genesis. Recently, our group showed that the MYC-containing dmin in leukemia cases arise by excision and amplification (episome model). In the present paper we investigated 10 cell lines from solid tumors showing MYCN amplification as dmin or hsr. Particularly revealing results were provided by the two subclones of the neuroblastoma cell line STA-NB-10, one showing dmin-only and the second hsr-only amplification. Both subclones showed a deletion, at 2p24.3, whose extension matched the amplicon extension. Additionally, the amplicon structure of the dmin and hsr forms was identical. This strongly argues that the episome model, already demonstrated in leukemias, applies to solid tumors as well, and that dmin and hsr are two faces of the same coin. The organization of the duplicated segments varied from very simple (no apparent changes from the normal sequence) to very complex. MYCN was always overexpressed (significantly overexpressed in three cases). The fusion junctions, always mediated by nonhomologous end joining, occasionally juxtaposed truncated genes in the same transcriptional orientation. Fusion transcripts involving NBAS (also known as NAG), FAM49A, BC035112 (also known as NCRNA00276), and SMC6 genes were indeed detected, although their role in the context of the tumor is not clear.
Footnotes
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↵8 Corresponding author.
E-mail rocchi{at}biologia.uniba.it.
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[Supplemental material is available online at http://www.genome.org. Sequence data from this study have been submitted to GenBank (http://www.ncbi.nlm.nih.gov/genbank/) under accession nos. HM243501–HM243513, HM243515–HM243529, and HM358636. NimbleGen array CGH data have been submitted to the NCBI Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/) under accession no. GSE22279. Affymetrix CGH data have been submitted to ArrayExpress (http://www.ebi.ac.uk/microarray-as/ae/) under accession no. E-MEXP-2735.]
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Article published online before print. Article and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.106252.110.
- Received February 8, 2010.
- Accepted May 6, 2010.
- Copyright © 2010 by Cold Spring Harbor Laboratory Press