Article
Identification of candidate genes associated with malignant transformation of IDH-mutated low-grade astrocytomas using genome-wide copy number variation analysis
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Authors
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Tareq A. Juratli
- Klinik und Poliklinik für Neurochirurgie, Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden
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Kathrin D. Geiger
- Institut für Neuropathologie, Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden
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Dietmar Krex
- Klinik und Poliklinik für Neurochirurgie, Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden
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Gabriele Schackert
- Klinik und Poliklinik für Neurochirurgie, Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden
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Arnab Chakravarti
- Department of Radiation Oncology, The Ohio State University, Medical School, Columbus, Ohio, U.S.A.
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Tim Lautenschlaeger
- Department of Radiation Oncology, The Ohio State University, Medical School, Columbus, Ohio, U.S.A.
| Published: | May 13, 2014 |
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Outline
Text
Objective: To identify copy number variations (CNVs) between IDH-mutated 1p/19q non-codeleted low-grade astrocytomas (LGA) and their consecutive chemo and radiation naïve secondary glioblastomas (sGBM).
Method: LGA tissue, the consecutive sGBM, and matched blood samples were collected from seven glioma patients. Tissues were assessed for IDH1/2 mutations, MGMT promoter methylation, and 1p/19q-codeletion. Affymetrix Genome-Wide Human SNP Array 6.0 and Nexus (Biodiscovery) using SnpRank segmentation algorithm to identify CNVs were used. Twenty-five probes were required for a CNV to be called. For each segment, a minimum probe median of +0.2 (-0.2) was required to call a duplication (deletion). Genomic coordinates correspond to human genome build GRCh37 (ucsc hg19) and dbSNP build 131.
Results: Median follow-up was 11.4 years, median time to malignant progression 2.3 years (1.5-9.9 years) and median OS was 12.7 years (10.1-15.3 years). A total of 258 CNVs were identified comparing LGA vs. gDNA, 318 comparing sGBM vs. gDNA, and 427 comparing sGBM vs. LGA, including 460 amplifications, 510 deletions, and 33 LOH events. The most common CNV (4/7 patients) comparing sGBM vs. LGA was chr13:49521235-70694175, which was a deletion that was also seen in the same patients when using gDNA as reference. In one of the four patients the deletion was already present in the LGA. Using Ensembl biomart, 188 genes fall into this region. Other CNVs found in at least three individuals were chr18:61130792-61135806 (amplification), chr3:84631171-84669615 (deletion) and several separate CNVs in the region of chr9:0-11398649 (deletions).
Conclusions: We identified several regions putatively associated with IDH-mutated 1p/19q non-codeleted LGA progression to sGBM. Several genes were found in those regions, which have been previously reported to be associated with malignant transformation such as DOCK8, PTPRD, DMRT1 and CDH7. Importantly, several CNVs suggesting novel candidate genes involved in malignant transformation such as PCDH9 and 17, and RCBTB1 were identified in this analysis.
