J Cancer 2015; 6(10):984-989. doi:10.7150/jca.11371

Research Paper

Mutation Analysis of Nine Chordoma Specimens by Targeted Next-Generation Cancer Panel Sequencing

Carina Fischer1#, Susanne Scheipl3,5#, Agnes Zopf1, Norbert Niklas1, Alexander Deutsch4, Mette Jorgensen3, Birgit Lohberger5, Elke Verena Froehlich5, Andreas Leithner5, Christian Gabriel1, Bernadette Liegl-Atzwanger6, Beate Rinner2✉

1. Red Cross Transfusion Service for Upper Austria, Krankenhausstraße 7, 4020 Linz, Austria.
2. Center for Medical Research, Cell Culture Facility, Medical University of Graz, Stiftingtalstrasse 24, 8010 Graz, Austria.
3. University College London Cancer Institute, 72 Huntley Street, London, WC1 6BT, UK.
4. Division of Hematology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 38D, 8036 Graz, Austria.
5. Department of Orthopaedic Surgery, Medical University of Graz, Auenbruggerplatz 5, 8036 Graz, Austria.
6. Institute of Pathology, Medical University of Graz, Auenbruggerplatz 25, 8036 Graz, Austria
# C.F. and S.S. contributed equally to this paper

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Fischer C, Scheipl S, Zopf A, Niklas N, Deutsch A, Jorgensen M, Lohberger B, Froehlich EV, Leithner A, Gabriel C, Liegl-Atzwanger B, Rinner B. Mutation Analysis of Nine Chordoma Specimens by Targeted Next-Generation Cancer Panel Sequencing. J Cancer 2015; 6(10):984-989. doi:10.7150/jca.11371. Available from http://www.jcancer.org/v06p0984.htm

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Background: Chordoma is a rare primary malignant bone tumour. Treatment options are mainly restricted to surgical excision, since chordomas are largely resistant to conventional ionising radiation and chemotherapy. Thus, there is a strong need to gain more thorough insights into the molecular biology and genetics of chordoma to allow for the development of new therapeutic options. We performed an ultra-deep sequencing analysis to find novel mutations in cancer associated genes in chordomas to date unseen with Sanger sequencing.

Material and Methods: Nine chordomas (skull base (n=3), mobile spine (n=4), and sacrum/coccyx (n=2) were screened for mutations in 48 cancer genes using the Hot Spot Cancer Panel (Illumina). All putative mutations were compared against multiple databases (e.g. NCBI, COSMIC, PolyPhen, EGB, SIFT) and published Copy Number Variation (CNV) data for chordoma.

Results: Our results showed mutations with a frequency above 5% in tumorsuppressor- and onco-genes, revealing new possible driver genes for chordomas. We detected three different variants accounting for 11 point mutations in three cancer associated genes (KIT, KDR and TP53). None of the detected mutations was found in all samples investigated. However, all genes affected interact or are connected in pathway analysis. There were no correlations to already reported CNVs in the samples analysed.

Conclusions: We identified mutations in the associated genes KIT, KDR, and TP53. These mutations have been described previously and have been predicted to be tolerated. Further results on a larger series are warranted. The driver mechanisms of chordoma still have to be identified.

Keywords: chordoma, next-generation sequencing, copy number, somatic mutations, cancer panel