Journal Article

Deep whole-genome analysis of 494 hepatocellular carcinomas

Li, Zhixuan, Wang, Ruiru, Zhang, Yangqianwen, Wang, Yin, Bai, Jian, Wang, Yan, Gu, Jin, Gao, Dong, Yang, Shuai, Bao, Jinxia, Xue, Ruidong, Gao, Qiang, Jiang, Nanhai, Zhang, Ning, Wu, Lin, Wang, Xin Wei, Zheng, Bo, Hu, Ji, Liu, Mo, Wang, Wenwen, Zhu, Yanjing, Chen, Lei, Shen, Siyun, Bai, Fan, Nakagawa, Hidewaki, Liu, Ke, Rozen, Steven G., Wang, Hongyang, Yang, Airong, Bai, Mixue, Zhang, Chong

2024

Overview

Over half of hepatocellular carcinoma (HCC) cases diagnosed worldwide are in China 1 – 3 . However, whole-genome analysis of hepatitis B virus (HBV)-associated HCC in Chinese individuals is limited 4 – 8 , with current analyses of HCC mainly from non-HBV-enriched populations 9 , 10 . Here we initiated the Chinese Liver Cancer Atlas (CLCA) project and performed deep whole-genome sequencing (average depth, 120×) of 494 HCC tumours. We identified 6 coding and 28 non-coding previously undescribed driver candidates. Five previously undescribed mutational signatures were found, including aristolochic-acid-associated indel and doublet base signatures, and a single-base-substitution signature that we termed SBS_H8. Pentanucleotide context analysis and experimental validation confirmed that SBS_H8 was distinct to the aristolochic-acid-associated SBS22. Notably, HBV integrations could take the form of extrachromosomal circular DNA, resulting in elevated copy numbers and gene expression. Our high-depth data also enabled us to characterize subclonal clustered alterations, including chromothripsis, chromoplexy and kataegis, suggesting that these catastrophic events could also occur in late stages of hepatocarcinogenesis. Pathway analysis of all classes of alterations further linked non-coding mutations to dysregulation of liver metabolism. Finally, we performed in vitro and in vivo assays to show that fibrinogen alpha chain ( FGA ), determined as both a candidate coding and non-coding driver, regulates HCC progression and metastasis. Our CLCA study depicts a detailed genomic landscape and evolutionary history of HCC in Chinese individuals, providing important clinical implications. The Chinese Liver Cancer Atlas project depicts a panoramic genomic landscape of hepatocellular carcinoma, covering candidate coding and non-coding drivers, mutational signatures, extrachromosomal circular DNA, subclonal catastrophic events and detailed evolutionary history.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/51 / 631/181/2474 / 631/208/68 / 631/208/737 / 631/67/69 / 692/699/67/1504/1610 / Aristolochic Acids - metabolism / Carcinogenesis / Carcinoma, Hepatocellular - genetics / Carcinoma, Hepatocellular - virology / Catastrophic events / China / Chloride channels (calcium-gated) / Chromothripsis / Circular DNA / Disease Progression / DNA, Circular - genetics / East Asian People - genetics / Evolution, Molecular / Evolutionary genetics / Fibrinogen / Gene expression / Gene sequencing / Genome, Human - genetics / Genomes / Hepatitis B / Hepatitis B virus - genetics / Hepatocellular carcinoma / High-Throughput Nucleotide Sequencing / Humanities and Social Sciences / Humans / In vivo methods and tests / INDEL Mutation - genetics / Liver - metabolism / Liver cancer / Liver Neoplasms - genetics / Liver Neoplasms - virology / Metastases / multidisciplinary / Mutation / Mutation - genetics / Neoplasm Metastasis - genetics / Open Reading Frames - genetics / Reproducibility of Results / Science / Science (multidisciplinary) / Signatures / Tumors / Whole Genome Sequencing