Introduction: A set of genetic mutations to classify hepatocellular carcinoma (HCC) useful to clinical studies is an unmet need. Hepatitis B virus-related HCC (HBV-HCC) harbors a unique genetic mutation, namely the HBV integration, among other somatic endogenous gene mutations. We explored a combination of HBV DNA integrations and common somatic mutations to classify HBV-HCC by using a capture-sequencing platform. Methods: A total of 153 HBV-HCCs after surgical resection were subjected to capture-sequencing to identify HBV integrations and three common somatic mutations in genomes. Three mutually exclusive mutations, HBV DNA integration into the TERT promoter, HBV DNA integration into MLL4, or TERT promoter point mutation, were identified in HBV-HCC. Results: They were used to classify HBV-HCCs into four groups: G1 with HBV-TERT integration (25.5%); G2 with HBV-MLL4 integration (10.5%); G3 with TERT promoter mutation (30.1%); and G4 without these three mutations (34.0%). Clinically, G3 has the highest male-to-female ratio, cirrhosis rate and associated with higher early recurrence and mortality after resection, but G4 has the best outcome. Transcriptomic analysis revealed a grouping different from the published ones, and G2 with an active immune profile related to immune checkpoint inhibitor response. Analysis of integrated HBV DNA provided clues for HBV genotype and variants in carcinogenesis of different HCC subgroup. This new classification was also validated in another independent cohort. Discussion/Conclusion: A simple and robust genetic classification was developed to aid in understanding HBV-HCC and in harmonizing clinical studies.


中文翻译：

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HBV DNA 整合到端粒酶或 MLL4 基因和 TERT 启动子点突变作为具有不同特征的 HBV 相关 HCC 亚组中的三个独立特征


简介：对临床研究有用的一组用于对肝细胞癌 (HCC) 进行分类的基因突变的需求尚未得到满足。乙型肝炎病毒相关性肝癌（HBV-HCC）在其他体细胞内源性基因突变中存在一种独特的基因突变，即HBV整合。我们探索了 HBV DNA 整合和常见体细胞突变的组合，通过使用捕获测序平台对 HBV-HCC 进行分类。方法：对手术切除后的总共 153 个 HBV-HCC 进行捕获测序，以鉴定基因组中的 HBV 整合和三种常见体细胞突变。在 HBV-HCC 中发现了三种相互排斥的突变，即 HBV DNA 整合到 TERT 启动子中、HBV DNA 整合到 MLL4 中或 TERT 启动子点突变。结果：它们被用来将 HBV-HCC 分为四组：具有 HBV-TERT 整合的 G1 组（25.5%）； G2 具有 HBV-MLL4 整合（10.5%）； G3 具有 TERT 启动子突变（30.1%）；和没有这三个突变的 G4 (34.0%)。临床上，G3的男女比例、肝硬化发生率最高，并且与切除后较高的早期复发和死亡率相关，但G4的预后最好。转录组分析揭示了与已发表的分组不同的分组，G2 具有与免疫检查点抑制剂反应相关的活跃免疫特征。整合的 HBV DNA 分析为不同 HCC 亚组癌变中的 HBV 基因型和变异提供了线索。这种新的分类也在另一个独立队列中得到了验证。讨论/结论：开发了一种简单而强大的遗传分类，以帮助了解 HBV-HCC 并协调临床研究。