The EasyFuse tool predicts tumor-specific gene fusions and shows their immunogenicity as neoantigens.

  • Major Finding: The EasyFuse tool predicts tumor-specific gene fusions and shows their immunogenicity as neoantigens.

  • Concept: EasyFuse detects gene fusions in patient samples with high sensitivity and precision, outperforming current tools.

  • Impact: Data obtained using this tool can nominate targets for personalized cancer immunotherapies.

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Neoepitopes, derived from neoantigens, have been exploited as immunotherapy targets, but despite their potentially immunogenic nature, gene fusions (GF) have been underutilized in current immunotherapy development approaches. This is in large part due to the need for improved computational methods that provide more accurate and sensitive identification of cancer-specific GFs. Weber, Ibn-Salem, and colleagues developed a tool that uses transcriptome data to allow for the prediction of tumor-specific GFs in clinical samples which was termed “EasyFuse.” In breast tumor samples, a majority of GFs were in cis-near configuration (same chromosome, within 1 Mb on the same strand) and were found to be present in normal breast tissue as well as tumor tissue, suggesting their lack of tumor specificity. Conversely, trans-like GFs were more tumor specific, so EasyFuse was tailored for their identification through the introduction of a read-filtering step to increase the sensitivity needed for detecting these trans-like GFs. The application of this step reduced the percentage of predicted GFs present in normal breast tissue which provided for better tumor specificity. Comparison of EasyFuse with other currently available tools further supported its high sensitivity as well as its superior precision for trans-like GF prediction from clinically relevant formalin-fixed paraffin-embedded (FFPE) samples. Use of EasyFuse was then applied to 14 FFPE melanoma samples with 30 of the predicted fusion neoantigen candidates being assessed for CD4+ and CD8+ reactivity. A positive CD4+ T cell response was observed with 48% of these neoantigens while only 3% demonstrated a positive CD8+ T cell response. However, upon investigating the frequency of these neoantigens across 57 breast cancer tissue samples, most of the neoantigens were observed only in individual samples, suggesting that these immunogenic GF neoepitopes are not recurrent. Overall, this work provides a tool to reliably predict GFs in tumor samples from individual patients to facilitate their potential use as neoantigen targets for cancer immunotherapy approaches.

Weber D, Ibn-Salem J, Sorn P, Suchan M, Holtsträter C, Lahrmann U, et al. Accurate detection of tumor-specific gene fusions reveals strongly immunogenic personal neoantigens. Nat Biotechnol 2022 Apr 4 [Epub ahead of print].

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