Franziska Lang, Patrick Sorn, Martin Suchan, Alina Henrich, Christian Albrecht, Nina Köhl, Aline Beicht, Pablo Riesgo-Ferreiro, Christoph Holtsträter, Barbara Schrörs, David Weber, Martin Löwer, Ugur Sahin, Jonas Ibn-Salem
{"title":"从体细胞突变中预测肿瘤特异性剪接,作为新抗原候选源。","authors":"Franziska Lang, Patrick Sorn, Martin Suchan, Alina Henrich, Christian Albrecht, Nina Köhl, Aline Beicht, Pablo Riesgo-Ferreiro, Christoph Holtsträter, Barbara Schrörs, David Weber, Martin Löwer, Ugur Sahin, Jonas Ibn-Salem","doi":"10.1093/bioadv/vbae080","DOIUrl":null,"url":null,"abstract":"<p><strong>Motivation: </strong>Neoantigens are promising targets for cancer immunotherapies and might arise from alternative splicing. However, detecting tumor-specific splicing is challenging because many non-canonical splice junctions identified in tumors also appear in healthy tissues. To increase tumor-specificity, we focused on splicing caused by somatic mutations as a source for neoantigen candidates in individual patients.</p><p><strong>Results: </strong>We developed the tool splice2neo with multiple functionalities to integrate predicted splice effects from somatic mutations with splice junctions detected in tumor RNA-seq and to annotate the resulting transcript and peptide sequences. Additionally, we provide the tool EasyQuant for targeted RNA-seq read mapping to candidate splice junctions. Using a stringent detection rule, we predicted 1.7 splice junctions per patient as splice targets with a false discovery rate below 5% in a melanoma cohort. We confirmed tumor-specificity using independent, healthy tissue samples. Furthermore, using tumor-derived RNA, we confirmed individual exon-skipping events experimentally. Most target splice junctions encoded neoepitope candidates with predicted major histocompatibility complex (MHC)-I or MHC-II binding. Compared to neoepitope candidates from non-synonymous point mutations, the splicing-derived MHC-I neoepitope candidates had lower self-similarity to corresponding wild-type peptides. In conclusion, we demonstrate that identifying mutation-derived, tumor-specific splice junctions can lead to additional neoantigen candidates to expand the target repertoire for cancer immunotherapies.</p><p><strong>Availability and implementation: </strong>The R package splice2neo and the python package EasyQuant are available at https://github.com/TRON-Bioinformatics/splice2neo and https://github.com/TRON-Bioinformatics/easyquant, respectively.</p>","PeriodicalId":72368,"journal":{"name":"Bioinformatics advances","volume":null,"pages":null},"PeriodicalIF":2.4000,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11165244/pdf/","citationCount":"0","resultStr":"{\"title\":\"Prediction of tumor-specific splicing from somatic mutations as a source of neoantigen candidates.\",\"authors\":\"Franziska Lang, Patrick Sorn, Martin Suchan, Alina Henrich, Christian Albrecht, Nina Köhl, Aline Beicht, Pablo Riesgo-Ferreiro, Christoph Holtsträter, Barbara Schrörs, David Weber, Martin Löwer, Ugur Sahin, Jonas Ibn-Salem\",\"doi\":\"10.1093/bioadv/vbae080\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Motivation: </strong>Neoantigens are promising targets for cancer immunotherapies and might arise from alternative splicing. However, detecting tumor-specific splicing is challenging because many non-canonical splice junctions identified in tumors also appear in healthy tissues. To increase tumor-specificity, we focused on splicing caused by somatic mutations as a source for neoantigen candidates in individual patients.</p><p><strong>Results: </strong>We developed the tool splice2neo with multiple functionalities to integrate predicted splice effects from somatic mutations with splice junctions detected in tumor RNA-seq and to annotate the resulting transcript and peptide sequences. Additionally, we provide the tool EasyQuant for targeted RNA-seq read mapping to candidate splice junctions. Using a stringent detection rule, we predicted 1.7 splice junctions per patient as splice targets with a false discovery rate below 5% in a melanoma cohort. We confirmed tumor-specificity using independent, healthy tissue samples. Furthermore, using tumor-derived RNA, we confirmed individual exon-skipping events experimentally. Most target splice junctions encoded neoepitope candidates with predicted major histocompatibility complex (MHC)-I or MHC-II binding. Compared to neoepitope candidates from non-synonymous point mutations, the splicing-derived MHC-I neoepitope candidates had lower self-similarity to corresponding wild-type peptides. In conclusion, we demonstrate that identifying mutation-derived, tumor-specific splice junctions can lead to additional neoantigen candidates to expand the target repertoire for cancer immunotherapies.</p><p><strong>Availability and implementation: </strong>The R package splice2neo and the python package EasyQuant are available at https://github.com/TRON-Bioinformatics/splice2neo and https://github.com/TRON-Bioinformatics/easyquant, respectively.</p>\",\"PeriodicalId\":72368,\"journal\":{\"name\":\"Bioinformatics advances\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":2.4000,\"publicationDate\":\"2024-05-29\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11165244/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Bioinformatics advances\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1093/bioadv/vbae080\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q2\",\"JCRName\":\"MATHEMATICAL & COMPUTATIONAL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bioinformatics advances","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1093/bioadv/vbae080","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/1/1 0:00:00","PubModel":"eCollection","JCR":"Q2","JCRName":"MATHEMATICAL & COMPUTATIONAL BIOLOGY","Score":null,"Total":0}
Prediction of tumor-specific splicing from somatic mutations as a source of neoantigen candidates.
Motivation: Neoantigens are promising targets for cancer immunotherapies and might arise from alternative splicing. However, detecting tumor-specific splicing is challenging because many non-canonical splice junctions identified in tumors also appear in healthy tissues. To increase tumor-specificity, we focused on splicing caused by somatic mutations as a source for neoantigen candidates in individual patients.
Results: We developed the tool splice2neo with multiple functionalities to integrate predicted splice effects from somatic mutations with splice junctions detected in tumor RNA-seq and to annotate the resulting transcript and peptide sequences. Additionally, we provide the tool EasyQuant for targeted RNA-seq read mapping to candidate splice junctions. Using a stringent detection rule, we predicted 1.7 splice junctions per patient as splice targets with a false discovery rate below 5% in a melanoma cohort. We confirmed tumor-specificity using independent, healthy tissue samples. Furthermore, using tumor-derived RNA, we confirmed individual exon-skipping events experimentally. Most target splice junctions encoded neoepitope candidates with predicted major histocompatibility complex (MHC)-I or MHC-II binding. Compared to neoepitope candidates from non-synonymous point mutations, the splicing-derived MHC-I neoepitope candidates had lower self-similarity to corresponding wild-type peptides. In conclusion, we demonstrate that identifying mutation-derived, tumor-specific splice junctions can lead to additional neoantigen candidates to expand the target repertoire for cancer immunotherapies.
Availability and implementation: The R package splice2neo and the python package EasyQuant are available at https://github.com/TRON-Bioinformatics/splice2neo and https://github.com/TRON-Bioinformatics/easyquant, respectively.