Original 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 Koehl,Aline Beicht,Pablo Riesgo-Ferreiro,Christoph Holtsträter,Barbara Schrörs,David Weber,Martin Löwer,Ugur Sahin,Jonas Ibn-Salem
This article explores the dysregulation of splicing in tumors and its potential impact on cancer immunotherapy. Splicing is a process that produces different forms of RNA transcripts by removing certain sections of the transcript and joining the remaining segments together. In tumors, splicing can be disrupted, leading to the production of tumor-specific transcripts that encode neoantigens, or new targets for cancer immunotherapy.
Detecting these tumor-specific splicing events is challenging because similar non-canonical splice junctions can also be found in healthy tissues. To address this, the researchers developed a tool called splice2neo. This tool integrates predicted splice effects from somatic mutations with splice junctions detected in tumor RNA samples. It excludes splice junctions found in healthy tissues, annotates resulting transcript and peptide sequences, and re-quantifies supporting RNA-seq reads.
Using this approach, the researchers identified 1.7 tumor-specific splice junctions per tumor with a low false discovery rate in a melanoma cohort. They confirmed the tumor-specificity of these splice junctions using independent healthy tissue samples. Furthermore, they experimentally validated individual exon skipping events using tumor-derived RNA.
The researchers found that most of the identified splice junctions encoded neoepitope candidates, which are potential targets for cancer immunotherapy. These neoepitope candidates showed low similarity to corresponding wild-type peptides, making them promising candidates for expanding the repertoire of targets for cancer immunotherapies.
Overall, this study demonstrates that identifying tumor-specific splice junctions can uncover additional neoantigen candidates for cancer immunotherapy, providing new opportunities for treating cancer.
Original article: https://www.biorxiv.org/content/10.1101/2023.06.27.546494v2