Discovery of recurrent structural variants in nasopharyngeal carcinoma
- Anton Valouev1,5,6,
- Ziming Weng2,3,5,
- Robert T. Sweeney2,
- Sushama Varma2,
- Quynh-Thu Le4,
- Christina Kong2,
- Arend Sidow2,3,6 and
- Robert B. West2,6
- 1Division of Bioinformatics, Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, California 90087, USA;
- 2Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA;
- 3Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA;
- 4Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California 94305, USA
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↵5 These authors contributed equally to this work.
Abstract
We present the discovery of genes recurrently involved in structural variation in nasopharyngeal carcinoma (NPC) and the identification of a novel type of somatic structural variant. We identified the variants with high complexity mate-pair libraries and a novel computational algorithm specifically designed for tumor-normal comparisons, SMASH. SMASH combines signals from split reads and mate-pair discordance to detect somatic structural variants. We demonstrate a >90% validation rate and a breakpoint reconstruction accuracy of 3 bp by Sanger sequencing. Our approach identified three in-frame gene fusions (YAP1-MAML2, PTPLB-RSRC1, and SP3-PTK2) that had strong levels of expression in corresponding NPC tissues. We found two cases of a novel type of structural variant, which we call “coupled inversion,” one of which produced the YAP1-MAML2 fusion. To investigate whether the identified fusion genes are recurrent, we performed fluorescent in situ hybridization (FISH) to screen 196 independent NPC cases. We observed recurrent rearrangements of MAML2 (three cases), PTK2 (six cases), and SP3 (two cases), corresponding to a combined rate of structural variation recurrence of 6% among tested NPC tissues.
Footnotes
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↵6 Corresponding authors
E-mail valouev{at}usc.edu
E-mail arend{at}stanford.edu
E-mail rbwest{at}stanford.edu
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.156224.113.
- Received February 14, 2013.
- Accepted October 7, 2013.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 3.0 Unported), as described at http://creativecommons.org/licenses/by-nc/3.0/.
