Accurate and efficient detection of gene fusions from RNA sequencing data
- Sebastian Uhrig1,2,3,4,
- Julia Ellermann4,5,
- Tatjana Walther5,
- Pauline Burkhardt1,3,4,
- Martina Fröhlich1,2,3,
- Barbara Hutter1,2,3,
- Umut H. Toprak3,6,
- Olaf Neumann7,
- Albrecht Stenzinger3,7,8,
- Claudia Scholl3,9,
- Stefan Fröhling3,5,10 and
- Benedikt Brors1,3,10
- 1Division of Applied Bioinformatics, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT) Heidelberg, 69120 Heidelberg, Germany;
- 2Computational Oncology Group, Molecular Diagnostics Program at the NCT and DKFZ, 69120 Heidelberg, Germany;
- 3German Cancer Consortium (DKTK), 69120 Heidelberg, Germany;
- 4Faculty of Biosciences, Heidelberg University, 69120 Heidelberg, Germany;
- 5Division of Translational Medical Oncology, NCT Heidelberg and DKFZ, 69120 Heidelberg, Germany;
- 6Division of Neuroblastoma Genomics, DKFZ, 69120 Heidelberg, Germany;
- 7Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany;
- 8German Center for Lung Research (DZL), Heidelberg site, 69120 Heidelberg, Germany;
- 9Division of Applied Functional Genomics, DKFZ and NCT Heidelberg, 69120 Heidelberg, Germany;
- 10NCT Molecular Diagnostics Program, NCT Heidelberg and DKFZ, 69120 Heidelberg, Germany
Abstract
The identification of gene fusions from RNA sequencing data is a routine task in cancer research and precision oncology. However, despite the availability of many computational tools, fusion detection remains challenging. Existing methods suffer from poor prediction accuracy and are computationally demanding. We developed Arriba, a novel fusion detection algorithm with high sensitivity and short runtime. When applied to a large collection of published pancreatic cancer samples (n = 803), Arriba identified a variety of driver fusions, many of which affected druggable proteins, including ALK, BRAF, FGFR2, NRG1, NTRK1, NTRK3, RET, and ROS1. The fusions were significantly associated with KRAS wild-type tumors and involved proteins stimulating the MAPK signaling pathway, suggesting that they substitute for activating mutations in KRAS. In addition, we confirmed the transforming potential of two novel fusions, RRBP1-RAF1 and RASGRP1-ATP1A1, in cellular assays. These results show Arriba's utility in both basic cancer research and clinical translation.
Footnotes
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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 https://www.genome.org/cgi/doi/10.1101/gr.257246.119.
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Freely available online through the Genome Research Open Access option.
- Received September 18, 2019.
- Accepted December 30, 2020.
This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
