背景:基因组改变在癌症的发展中起重要作用。我们探讨了蛋白质编码基因和转录变化对台湾肝细胞癌(HCC)患者临床和分子改变的影响。
方法:我们分析了147个HCC的全外显子组测序和100个RNA测序数据集,并将它们与癌症基因组图谱(TCGA)-肝细胞癌队列进行比较,并开发了一组81个凋亡相关基因用于分子分类。
结果:TERT(50%),TP53(25%),CTNNB1(14%),ARID1A(12%),和KMT2C(11%)是癌症相关基因最常见的遗传改变。ALDH2和KMT2C在我们队列中的突变频率远高于TCGA,而CTNNB1仅在14%的台湾患者中发现。还观察到APOBEC突变特征和与草药药物相关的马兜铃酸相关特征中ALDH2的高种系突变率。当我们使用凋亡相关基因进行分子分类时,确定了HCC的A和B组。后一组,生存结果较差,有更多的aDC,CD4+Tem,巨噬细胞M2,NKT,浆细胞,和Th1细胞,和较少的CD4+记忆T细胞,CD8+Tcm,cDC,iDC,和Th2细胞,以及更多的染色体间融合基因。代谢组学分析显示有54例HBV感染。此外,我们发现HBV整合的主要靶基因是ALB。
结论:在我们的台湾HCC患者中观察到独特的基因组改变。使用凋亡相关基因的分子分类可能导致HCC的新治疗方法。
BACKGROUND: Genomic alterations play important roles in the development of cancer. We explored the impact of protein-coding genes and transcriptomic changes on clinical and molecular alterations in Taiwanese hepatocellular carcinoma (HCC) patients.
METHODS: We analyzed 147 whole-exome sequencing and 100 RNA sequencing datasets of HCC and compared them with The Cancer Genome Atlas (TCGA)-Liver Hepatocellular Carcinoma cohort and develop a panel of 81 apoptosis-related genes for molecular classification.
RESULTS: TERT (50%), TP53 (25%), CTNNB1 (14%), ARID1A (12%), and KMT2C (11%) were the most common genetic alterations of cancer-related genes. ALDH2 and KMT2C mutated at much higher frequencies in our cohort than in TCGA, whereas CTNNB1 was found only in 14% of our Taiwanese patients. A high germline mutation rate of ALDH2 in the APOBEC mutational signature and herb drug-related aristolochic acid-associated signature was also observed. Groups A and B of HCC were identified when we used apoptosis-related genes for molecular classification. The latter group, which had poorer survival outcomes, had significantly more aDC, CD4+ Tem, macrophages M2, NKT, plasma cells, and Th1 cells, and less CD4+ memory T cells, CD8+ Tcm, cDC, iDC, and Th2 cells, as well as more inter-chromosome fusion genes. Metatranscriptomic analysis revealed 54 cases of HBV infection. Moreover, we found that the main target gene of HBV integration is ALB.
CONCLUSIONS: Unique genomic alterations were observed in our Taiwanese HCC patients. Molecular classification using apoptosis-related genes could lead to new therapeutic approaches for HCC.