Long-read sequencing reveals widespread novel splicing and neojunction-derived neoantigens in nasopharyngeal carcinoma

Cancer research · Nasopharyngeal carcinoma

We identify a substantial number of full‑length novel transcripts (22,687; ~44.38%).

The widespread transcriptomic diversity driven by alternative splicing (AS) contributes to all hallmarks of cancer and represents a critical source of neoantigens for personalized immunotherapy. However, unlike other major malignancies, the full repertoire of AS in nasopharyngeal carcinoma (NPC) remains underexplored. Here, we employ long‑read sequencing (LR‑seq) to generate a high‑resolution, isoform‑level transcriptomic atlas from a cohort of 14 NPC tumor samples and four immortalized nasopharyngeal epithelial cell lines. We identify a substantial number of full‑length novel transcripts (22,687; ~44.38%), which reveal diverse splicing patterns and previously unannotated splicing events. By integrating short‑read RNA‑seq data to quantify isoform expression, we discover a subset of novel transcripts that are differentially expressed between tumor samples and immortalized nasopharyngeal epithelial cell lines. Furthermore, LR‑seq enables precise identification of chimeric readthrough fusion transcripts, such as CLDN15‑FIS1 and FOXRED2‑TXN2. Finally, we develop a computational framework, tumor‑specific splicing neoantigen detection (TS‑SNAD), to predict neoantigens originating from novel exon‑exon junctions (neojunctions) in tumor‑specific novel transcripts. Using this framework, we identify neojunction‑derived neoantigens and experimentally validate the immunogenicity of selected HLA‑B*40:01‑restricted neoantigens. These neojunction‑derived peptides constitute a new class of noncanonical neoantigens with significant potential for developing personalized cancer vaccines for NPC.

Evidence level: Korai humán adat. Kis vagy feltáró emberi adat.

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