简介:基因组分析彻底改变了肝癌的治疗干预和临床管理。然而,致病机制,复发的分子决定因素,对于肝癌一线治疗(抗PD-(L)1加贝伐单抗)的预测性生物标志物仍未完全了解。材料和方法:靶向下一代测序(tNGS)(603癌症基因组)用于232肝细胞癌(HCC)和22肝内胆管癌(ICC)患者的基因组谱分析。其中47例无法切除/转移性HCC患者接受抗PD-1+贝伐单抗治疗.估计基因组改变与血管浸润的关联(VI),发病的位置,复发,总生存期(OS),无复发生存率(RFS),和抗PD-1加贝伐单抗治疗反应。结果:基因组景观显示,肝癌中最常见的改变基因是TP53,FAT3,PDE4DIP,KMT2C,FAT1和MYO18A,而TP53,FAT1,FAT3,PDE4DIP,ROS1和GALNT11在ICC中经常发生改变;值得注意的是,KRAS(18.18%vs.1.29%)和BAP1(13.64%与1.29%)的改变在ICC中明显更普遍。比较分析表明中国和西方HCC队列之间的不同临床病理/基因组特征。VI基础肝癌的基因组分析显示,LDLR,MSH2,KDM5D,PDE3A,与没有VI的患者相比,VI组的FOXO1经常发生改变。与HCC患者的右肝叶相比,肝癌患者的左肝叶OS较高(中位OS:36.77个月vs.未达到,p<0.05)。通过进一步的比较,Notch信号通路相关的改变在HCC患者的右肝叶中明显普遍存在。值得注意的是,多因素Cox回归分析显示RB1、NOTCH3、MGA、SYNE1和ZFHX3作为独立的预后因素,与HCC患者的OS显著相关。此外,改变的LATS1在HCC复发组中丰富,令人印象深刻的是,在预测RFS时,它独立于临床病理特征(改变型的中位RFS与野生型:5.57个月vs.22.47个月,p<0.01)。关于那些接受治疗的HCC患者,TMB值,改变的PTPRZ1和细胞周期相关的改变被确定为与客观反应率(ORR)正相关,但KMT2D改变与ORR呈负相关。此外,改变的KMT2D和细胞周期信号与无进展生存期(PFS)的时间减少和增加显着相关,分别。结论:全面的基因组谱分析破译了VI的独特分子特征,发病的位置,复发,和肝癌的生存时间。肝癌中抗PD-1加贝伐单抗反应的新遗传预测因子的鉴定促进了循证治疗方法的发展。
Introduction: Genomic profiling has revolutionized therapeutic interventions and the clinical management of liver cancer. However, pathogenetic mechanisms, molecular determinants of recurrence, and predictive biomarkers for first-line treatment (anti-PD-(L)1 plus bevacizumab) in liver cancer remain incompletely understood. Materials and methods: Targeted next-generation sequencing (tNGS) (a 603-cancer-gene panel) was applied for the genomic profiling of 232 hepatocellular carcinoma (HCC) and 22 intrahepatic cholangiocarcinoma (ICC) patients, among which 47 unresectable/metastatic HCC patients underwent anti-PD-1 plus bevacizumab therapy. Genomic alterations were estimated for their association with vascular invasion (VI), location of onset, recurrence, overall survival (OS), recurrence-free survival (RFS), and anti-PD-1 plus bevacizumab therapy response. Results: The genomic landscape exhibited that the most commonly altered genes in HCC were TP53, FAT3, PDE4DIP, KMT2C, FAT1, and MYO18A, while TP53, FAT1, FAT3, PDE4DIP, ROS1, and GALNT11 were frequently altered in ICC; notably, KRAS (18.18% vs. 1.29%) and BAP1 (13.64% vs. 1.29%) alterations were significantly more prevalent in ICC. Comparison analysis demonstrated the distinct clinicopathological/genomic characterizations between Chinese and Western HCC cohorts. Genomic profiling of HCC underlying VI showed that LDLR, MSH2, KDM5D, PDE3A, and FOXO1 were frequently altered in the VI group compared to patients without VIs. Compared to the right hepatic lobes of HCC patients, the left hepatic lobe of HCC patients had superior OS (median OS: 36.77 months vs. unreached, p < 0.05). By further comparison, Notch signaling pathway-related alterations were significantly prevalent among the right hepatic lobes of HCC patients. Of note, multivariate Cox regression analysis showed that altered RB1, NOTCH3, MGA, SYNE1, and ZFHX3, as independent prognostic factors, were significantly correlated with the OS of HCC patients. Furthermore, altered LATS1 was abundantly enriched in the HCC-recurrent group, and impressively, it was independent of clinicopathological features in predicting RFS (median RFS of altered type vs. wild-type: 5.57 months vs. 22.47 months, p < 0.01). Regarding those treated HCC patients, TMB value, altered PTPRZ1, and cell cycle-related alterations were identified to be positively associated with the objective response rate (ORR), but KMT2D alterations were negatively correlated with ORR. In addition, altered KMT2D and cell cycle signaling were significantly associated with reduced and increased time to progression-free survival (PFS), respectively. Conclusion: Comprehensive genomic profiling deciphered distinct molecular characterizations underlying VI, location of onset, recurrence, and survival time in liver cancer. The identification of novel genetic predictors of response to anti-PD-1 plus bevacizumab in HCC facilitated the development of an evidence-based approach to therapy.