Fusion transcripts landscape in hepatocellular carcinoma and potential impact on the expression of fusion partners

Fusion transcripts (FTs) are RNA molecules, also known as chimeric transcripts, formed through chromosomal rearrangements or transcriptional processes, contributing to tumorigenesis. This study systematically examined tumour-specific FTs in hepatocellular carcinoma (HCC) using high-throughput RNA sequencing data from independent datasets and The Cancer Genome Atlas (TCGA). Our <i>meta cohort</i> analysis included 328 HCC samples. Using STAR-Fusion, we identified 15 novel tumour-specific FTs, with SERPINA1-H19 as the most recurrent fusion event. Comparative expression analysis of fusion partner genes revealed significant downregulation in HCC tumours relative to normal adjacent liver tissues (NAT). We validated the expression levels of the key partner genes with 436 TCGA samples serving as an <i>in silico validation cohort</i> and in <i>wet lab validation cohorts</i> with 42 samples. ALB, APOA2, IGF2, MT2A, SERPINA1, and H19, which are key liver-associated genes, were frequently involved in tumour-specific fusion events suggesting either a loss of tumour suppressor property or gaining a novel function playing a role in hepatocarcinogenesis. Detailed characterization of SERPINA1-H19 identified 16 transcript variants with distinct structural modifications that may impact its functional output. Furthermore, low expression of SERPINA1 and H19 was associated with more aggressive HCC phenotypes. Overall, this study established a comprehensive repository of FTs for the first time, offering valuable insights into their role in HCC and their potential to serve as diagnostic and prognostic biomarkers for HCC.

融合转录本（Fusion transcripts, FTs）又称嵌合转录本（chimeric transcripts），是通过染色体重排或转录过程形成的RNA分子，可促进肿瘤发生。本研究依托独立数据集与癌症基因组图谱（The Cancer Genome Atlas, TCGA）的高通量RNA测序数据，对肝细胞癌（hepatocellular carcinoma, HCC）中的肿瘤特异性融合转录本进行了系统性分析。本研究的荟萃队列（meta cohort）共纳入328例肝细胞癌样本。借助STAR-Fusion工具，本研究鉴定出15种新型肿瘤特异性融合转录本，其中SERPINA1-H19为最频发的融合事件。对融合伴侣基因的表达对比分析显示，相较于癌旁正常肝组织（normal adjacent liver tissues, NAT），肝细胞癌组织中的融合伴侣基因表达显著下调。本研究分别通过由436例TCGA样本组成的计算机验证队列（in silico validation cohort），以及包含42例样本的湿实验验证队列（wet lab validation cohorts），验证了关键融合伴侣基因的表达水平。ALB、APOA2、IGF2、MT2A、SERPINA1及H19作为核心肝脏相关基因，频繁参与肿瘤特异性融合事件，提示其或发生抑癌特性缺失，或获得新功能，进而在肝细胞癌变过程中发挥作用。对SERPINA1-H19的详细表征发现，其存在16种具有独特结构修饰的转录本变体，这些结构修饰可能影响其功能产出。此外，SERPINA1与H19的低表达与更具侵袭性的肝细胞癌表型显著相关。综上，本研究首次构建了融合转录本的综合性数据库，为阐明融合转录本在肝细胞癌中的作用，以及其作为肝细胞癌诊断与预后生物标志物的潜在价值提供了关键见解。