The widespread transcriptomic diversity driven by alternative splicing 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 alternative splicing events 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 read-through 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 neoantigens restricted by HLA-B*40:01. These neojunction-derived peptides constitute a new class of noncanonical neoantigens with significant potential for developing personalized cancer vaccines for NPC.
Yi Shuai, Hualiang Yao, Bo Wang et al.· Genome Research· 0 citations
Chromatin remodeling comprises a set of molecular mechanisms that regulate gene transcription, DNA replication, and DNA repair by altering nucleosome structure. Previous studies have found that chromatin remodelers are heavily mutated in cancer patients, and targeting aberrant chromatin remodeling activities holds great potential for clinical benefit. Despite these promising findings, several significant hurdles remain before this strategy can be successfully transitioned from bench to bedside. The classic concept of chromatin remodeling focuses on the linear 2D chromatin structural level. While the emergence of sophisticated sequencing modalities has underscored the significance of 3D chromatin architecture, the mechanistic underpinnings and broader implications for cancer biology continue to be largely elusive. This review provides a comprehensive synthesis of the mechanisms and functional roles of classical chromatin remodelers within both physiological and neoplastic contexts. Furthermore, we integrate emerging insights regarding the cohesin complex as a primary mediator of three-dimensional (3D) genomic organization. By proposing a hierarchical framework that distinguishes between 'first-level' (classical) and 'higher-order' chromatin remodeling, we aim to provide a more holistic understanding of the integrated regulatory networks governing chromatin architecture. Furthermore, we have systematically cataloged the landscape of therapeutic strategies targeting chromatin remodelers in oncology. By evaluating the divergence between clinically approved therapies and those currently in developmental pipelines, we delineate the primary challenges confronting the field and propose strategic directions for future research. Collectively, we have delineated the multifaceted contributions of chromatin remodeling to cancer progression. The strategic modulation of these remodeling processes represents a vital frontier in the development of novel therapeutic interventions and is likely to emerge as a primary focus for future cancer management strategies.
