RNA biotype-associated molecular classification in hepatitis B-related hepatocellular carcinoma

Recent advance of RNA-seq technology enabled us to profile the diverse variations of RNA transcripts precisely, including the variants from alternative splicing as well as non-coding transcripts. Here, by performing transcriptome profiling including coding and noncoding transcripts, we identify four molecular subtypes of hepatitis B-related hepatocellular carcinoma (HCC) patients that are characterized by enriched expression of the RNA biotypes of noncoding (NC) and immune-related transcripts (IM) (i.e., IM+NC+, IM-NC+, IM+NC-, IM-NC-). The subtype IM+NC+ shows better prognostic outcome, while the subtype IM+NC- shows the worst prognostic outcome, respectively. Further interrogation of the subtypes identifies long noncoding transcripts (i.e., LINC00844, C3P1, and TRPG1-AS1) as well as an alternatively spliced event of USO1 that play pivotal roles in HCC progression. In addition, we report an oncogenic fusion transcript SLC39A14-PIWIL2 that promotes an aggressive phenotype of HCC. Our comprehensive and systematic analysis of HCC transcriptome identify RNA biotype-based molecular classification, revealing novel driver transcriptome variants that can be potential biomarkers and/or therapeutic targets for precision medicine. Overall design: Transcriptome profiling from 68 cases of HCC tissues and 10 adjacent non-tumoral tissues were performed. Four subtypes: S1: IM+NC+ S2: IM-NC+ S3: IM+NC- S4: IM-NC-

RNA测序（RNA-seq）技术的最新进展，使得我们能够精准解析RNA转录本的各类变异谱，包括可变剪接产生的变异体与非编码转录本。本研究通过对编码与非编码转录本开展转录组分析，鉴定出乙型肝炎相关肝细胞癌（hepatocellular carcinoma, HCC）患者的四种分子亚型，其特征为非编码（NC）与免疫相关转录本（IM）两类RNA生物型的表达富集，即IM+NC+、IM-NC+、IM+NC-、IM-NC-四种亚型。其中IM+NC+亚型预后较好，IM+NC-亚型则预后最差。对各亚型的深入解析发现，长链非编码转录本（如LINC00844、C3P1及TRPG1-AS1）以及USO1基因的可变剪接事件，在肝细胞癌进展中发挥关键调控作用。此外，本研究还报道了一种致癌融合转录本SLC39A14-PIWIL2，其可促进肝细胞癌的侵袭性表型。本研究通过对肝细胞癌转录组的全面系统分析，建立了基于RNA生物型的分子分型体系，并揭示了全新的驱动性转录组变异，这些变异可作为精准医学潜在的生物标志物与治疗靶点。实验设计：本研究对68例肝细胞癌组织及10例配对癌旁正常组织开展了转录组测序分析。四种亚型分别为：S1：IM+NC+、S2：IM-NC+、S3：IM+NC-、S4：IM-NC-