© Copyright 2008 by the Society for Neuro-Oncology
Received August 29, 2008
Accepted January 12, 2009
Basic and Translational Investigations
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Characterization of novel and complex genomic aberrations in glioblastoma using a 32K BAC array
Helena Nord 1,
Christian Hartmann 2,
Robin Andersson 3,
Uwe Menzel 1,
Susan Pfeifer 4,
Arkadiusz Piotrowski 5,
Adam Bogdan 6,
Wojciech Kloc 7,
Johanna Sandgren 8,
Tommie Olofsson 1,
Göran Hesselager 9,
Erik Blomquist 10,
Jan Komorowski 3,
Andreas von Deimling 2,
Carl E. G. Bruder 11,
Jan P. Dumanski 12,
Teresita Díaz de Ståhl 1*
1 Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
2 Department of Neuropathology, Heidelberg University, Heidelberg, Germany; Clinical Cooperation Unit Neuropathology, German Cancer Research Center, Heidelberg, Germany
3 Linnaeus Centre for Bioinformatics, Uppsala University, Uppsala, Sweden
4 Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden; Department of Women’s and Children’s Health, Uppsala Academic Hospital, Uppsala University, Uppsala, Sweden
5 Department of Genetics, University of Alabama at Birmingham School of Medicine, Birmingham, AL, USA; Department of Biology and Pharmaceutical Botany, Medical University of Gdansk, Gdansk, Poland
6 Department of Biology and Pharmaceutical Botany, Medical University of Gdansk, Gdansk, Poland
7 Department of Neurosurgery, Pomeranian Traumatology Center, Mikolaj Kopernik Regional Specialist Hospital, Gdansk, Poland; Department of Medical Sciences, University of Warmia and Mazury, Olsztyn, Poland
8 Department of Surgical Sciences, Uppsala Academic Hospital, Uppsala University, Uppsala, Sweden
9 Department of Neuroscience, Uppsala Academic Hospital, Uppsala University, Uppsala, Sweden
10 Department of Oncology, Radiology, and Clinical Immunology, Uppsala Academic Hospital, Uppsala University, Uppsala, Sweden
11 Southern Research Institute, Birmingham, AL, USA
12 Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden; Department of Genetics, University of Alabama at Birmingham School of Medicine, Birmingham, AL, USA
* To whom correspondence should be addressed. E-mail: teresita.diaz_de_stahl{at}genpat.uu.se.
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Abstract |
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Glioblastomas (GBs) are malignant central nervous system tumors often associated with devastating symptoms. Patients with GB have a very poor prognosis and despite treatment most of them die within 12 months from diagnosis. Several pathways such as the RAS, TP53 and PIK3 as well as the cell cycle control have been identified to be disrupted in this tumor. However, emerging data suggest that these aberrations only represent a fraction of the genetic changes involved in gliomagenesis. In this study, we have applied a 32K clone-based genomic array, covering 99% of the current assembly of the human genome to the detailed profiling of a set of 78 GBs. Complex patterns of aberrations including high and narrow copy number amplicons as well as a number of homozygously deleted loci were identified. Amplicons which varied both in number (3 in average) and size (average 1.4 Mb) were frequently detected (79% of the samples). The loci encompassed not only previously reported oncogenes (as EGFR, PDGFRA, MDM2, CDK4) but also numerous novel genes as GBR10, MKLN1, PPARGC1A, HGF, NAV3,CNTN1,SYT1 and ADAMTSL3. BNC2, PTPLAD2 and PTPRE represent candidate tumor suppressor genes encompassed within homozygously deleted loci. Many of these genes are already linked to several forms of cancer; others represent new candidate genes that may serve as prognostic markers or even as therapeutic targets in the future. The large individual variation observed between the samples demonstrates the underlying complexity of the disease and strengthens the demand for an individualized therapy based on the genetic profile of the patient.
Key Words:
Glioblastoma, Array-CGH, Cancer, Deletion, Amplification
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