基于基因组突变数据分析肝癌预后分子标志物

目的探讨肿瘤突变负荷(tumor mutational burden,TMB)及关键信号通路的基因变异与肝细胞癌(hepatocellular carcinoma,HCC)患者预后的相关性。方法从TCGA数据库及cBioPortal数据库schulze2015队列分别获取376例和243例HCC患者全外显子测序数据,从ICGC数据库获取JP队列 394例及FR 队列250例HCC患者全基因组测序数据。采用生存分析研究TMB、关键信号通路的基因变异与HCC患者预后的关系。结果 TCGA队列、JP队列、schulze2015队列和FR队列中,对数转换后的TMB与年龄均呈正相关(P<0.001);在schulze2015队列中,对数转换后的TMB与肿瘤大小呈正相关(r=0.204,P=0.002)。在TCGA队列中,与低TMB组比较,高TMB 组HCC患者的OS(P<0.001)及DFS(P=0.088)均明显降低,高TMB组HCC患者的死亡风险是低TMB组的2.156倍(P<0.001)。JP队列和FR队列均未发现TMB与OS及DFS有统计学意义。TCGA队列、JP队列和FR队列中,细胞周期调控通路基因变异的HCC患者中位DFS和中位OS均低于无变异的患者(P<0.05),而复发风险和死亡风险均高于无变异患者(P<0.05)。结论肿瘤突变负荷高和细胞周期调控通路的基因变异的HCC患者预后较差。

Genomic analysis revealed new prognosis signature in hepatocellular carcinoma

Objective To explore the effects of tumor mutational burden（TMB） and the genetic aberrations in key signal pathway genes on survival prognosis of hepatocellular carcinoma（HCC）. Methods The whole exon sequencing data of 376  and 243 HCC patients were downloaded from the TCGA and schulze2015 cohort of cBioPortal，respectively. Whole genome sequencing data of 394 patients of JP and 250 patients of FR were obtained from ICGC. The relationship of TMB and genetic aberrations in key signal pathway genes and prognosis in HCC patients was analyzed by survival analysis. Results In the TCGA，JP，schulze2015 and FR cohorts，TMB after logarithmic transformation was correlated with age（P<0.001）.In schulze2015，TMB after logarithmic transformation was correlated with tumor size（r=0.204，P=0.002）. In TCGA，OS and DFS of HCC patients in the high TMB group were significantly lower than those in the low TMB group（P<0.001，P＝0.088）. The risk of death in HCC patients in the high TMB group was 2.156 times higher than that in the low TMB group（P<0.001）.There was no association between TMB and OS and DFS in both JP and FR. In TCGA，JP，and FR cohorts，it was found that the median DFS，OS of HCC patients with genetic aberrations in cell cycle control pathway genes were lower than those without variation（P<0.05），while the risk of recurrence and death of HCC patients with genetic aberrations in cell cycle control pathway genes were higher than those without variation（P<0.05）. Conclusion High TMB  and genetic aberrations in cell cycle control pathway genes were associated with poor prognosis in HCC patients.