Abstract
Cancer-associated gene fusions are a potential source for highly immunogenic neoantigens, but the lack of computational tools for accurate, sensitive identification of personal gene fusions has limited their targeting in personalized cancer immunotherapy. Here we present EasyFuse, a machine learning computational pipeline for detecting cancer-specific gene fusions in transcriptome data obtained from human cancer samples. EasyFuse predicts personal gene fusions with high precision and sensitivity, outperforming previously described tools. By testing immunogenicity with autologous blood lymphocytes from patients with cancer, we detected pre-established CD4+ and CD8+ T cell responses for 10 of 21 (48%) and for 1 of 30 (3%) identified gene fusions, respectively. The high frequency of T cell responses detected in patients with cancer supports the relevance of individual gene fusions as neoantigens that might be targeted in personalized immunotherapies, especially for tumors with low mutation burden.
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Data availability
Sequence data from this study have been deposited in the Sequence Read Archive (SRA accession, used in Figs. 1, 2 and 3; NCBI BioProject ID PRJNA764684, used in Fig. 2) or the European Genome-phenome Archive (EGA accession EGAS00001004877, used in Figs. 4 and 5). Previously published sequencing data (immunogenicity cohort, Fig. 5, samples 10–14) are available in the EGA (EGA accession EGAD00001004455). Previously sequenced cell line data used in Fig. 1 are available at SRA accession PRJNA543964. Raw predicted GFs for all samples are available on Figshare (https://doi.org/10.6084/m9.figshare.19087049). Source data are provided with this paper.
Code availability
The source code and documentation of EasyFuse is available at GitHub (https://github.com/TRON-Bioinformatics/easyfuse).
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Acknowledgements
We thank the multicentre phase I study NCT02035956 and the RB_T002 research program (DRKS-ID: DRKS00011790) patients, from whom analyzed samples were obtained, and we thank the involved study site teams for their support and collaboration. We thank K. Chu and C. Büchner for proofreading and assistance with the manuscript. We thank O. Akilli-Oeztuerk for support with biosampling, R. Siek for support with installation of tools and setup on our servers and C. Ritzel for testing of EasyFuse pipeline and Docker image. Furthermore, we thank S. G. Maurici for technical support with RT–qPCR analysis and A. Henrich, S. Burchard and P. D. Dinh for technical support with the RNA sequencing. This work was supported by a European Research Council Advanced Grant to U.S. (ERC-AdG 789256).
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U.S. conceptualized the work and strategy. D.W., J.I., M.S. and I.V. planned and analyzed experiments. K.S. and M.S. performed the experiments. D.W., J.I., P.S., C.H., U.L., B.S., F.L. and M.L. performed data analysis. D.W., J.I. and U.S. interpreted data and wrote the manuscript.
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U.S. is a board member and employee of BioNTech SE. U.L., K.S. and I.V. are employees of BioNTech SE. U.S. is chief executive officer and stock owner of BioNTech SE. U.S., K.S. and I.V. have securities in BioNTech SE. The remaining authors declare no competing interests.
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Supplementary Figs. 1–10 and associated legends
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Source Data Fig. 5e
Unprocessed raw image compilation of ELISpot plates. The example shown in 5e is presented in columns 10/11 for CD4.
Source Data Fig. 5e
Unprocessed raw image compilation of ELISpot plates. The example shown in 5e is presented in columns 10/11 for CD8.
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Weber, D., Ibn-Salem, J., Sorn, P. et al. Accurate detection of tumor-specific gene fusions reveals strongly immunogenic personal neo-antigens. Nat Biotechnol 40, 1276–1284 (2022). https://doi.org/10.1038/s41587-022-01247-9
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DOI: https://doi.org/10.1038/s41587-022-01247-9
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