The Landscape of Cell-Free HBV Integrations and Mutations in Cirrhosis and Hepatocellular Carcinoma Patients

作者：Zheng, Bo; Liu, Xiao-Long; Fan, Rong; Bai, Jian; Wen, Hao; Du, Lu-Tao; Jiang, Guo-Qing; Wang, Chun-Ying; Fan, Xiao-Tang; Ye, Yi-Nong; Qian, Yun-Song; Wang, Ying-Chao; Liu, Gao-Jing; Deng, Guo-Hong; Shen, Feng; Hu, He-Ping; Wang, Hui; Zhang, Qing-Zheng; Ru, Lan-Lan; Zhang, Jing; Gao, Yan-Hang; Xia, Jie; Yan, Hua-Dong; Liang, Min-Feng; Yu, Yan-Long; Sun, Fu-Ming; Gao, Yu-Jing; Sun, Jian; Zhong, Chun-Xiu; Wang, Yin; Kong, Fei; Chen, Jin-Ming; Zheng, Dan; Yang, Yuan; Wang, Chuan-Xin; Wu, Lin

来源：Clinical Cancer Research, 2021, 27(13): 3772-3783.

DOI：10.1158/1078-0432.CCR-21-0002

• SINGLE-MOLECULE AMPLIFICATION
• CIRCULATING TUMOR DNA
• HEPATITIS-B
• RESEQUENCING TECHNOLOGY
• ASSOCIATION
• BIOMARKER
• SURVIVAL
• DISEASE
• PLASMA
• RISK

Purpose: Intratumoral hepatitis B virus (HBV) integrations and mutations are related to hepatocellular carcinoma (HCC) progression. Circulating cell-free DNA (cfDNA) has shown itself as a powerful noninvasive biomarker for cancer. However, the HBV integration and mutation landscape on cfDNA remains unclear. @@@ Experimental Design: A cSMART (Circulating Single-Molecule Amplification and Resequencing Technology)-based method (SIM) was developed to simultaneously investigate HBV integration and mutation landscapes on cfDNA with HBV-specific primers covering the whole HBV genome. Patients with HCC; (n = 481) and liver cirrhosis (LC; n - 517) were recruited in the study. @@@ Results: A total of 6,861 integration breakpoints induding TERT and KMT2B were discovered in HCC cfDNA, more than in LC. The concentration of circulating tumor DNA (ctDNA) was positively correlated with the detection rate of these integration hotspots and total HBV integration events in cfDNA. To track the origin of HBV integrations in cfDNA, whole-genome sequencing (WGS) was performed on their paired tumor tissues. The paired comparison of WGS data from tumor tissues and SIM data from cfDNA confirmed most recurrent integration events in cfDNA originated from tumor tissue. The mutational landscape across the whole HBV genome was first generated for both HBV genotype C and B. A region from nt1100 to nt1500 containing multiple HCC risk mutation sites (OR > 1) was identified as a potential HCC-related mutational hot zone. @@@ Conclusions: Our study provides an in-depth delineation of HBV integration/mutation landscapes at cfDNA level and did a comparative analysis with their paired tissues. These findings shed light on the possibilities of noninvasive detection of virus insertion/mutation.

• 单位
  内蒙古医学院; 佛山市第一人民医院; 1; 吉林大学; 山东大学; 华中科技大学; 中国科学院研究生院; 南方医科大学