Skip to main content
Journal cover image

Deep whole-genome analysis of 494 hepatocellular carcinomas.

Publication ,  Journal Article
Chen, L; Zhang, C; Xue, R; Liu, M; Bai, J; Bao, J; Wang, Y; Jiang, N; Li, Z; Wang, W; Wang, R; Zheng, B; Yang, A; Hu, J; Liu, K; Shen, S ...
Published in: Nature
March 2024

Over half of hepatocellular carcinoma (HCC) cases diagnosed worldwide are in China1-3. However, whole-genome analysis of hepatitis B virus (HBV)-associated HCC in Chinese individuals is limited4-8, with current analyses of HCC mainly from non-HBV-enriched populations9,10. 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.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Nature

DOI

EISSN

1476-4687

Publication Date

March 2024

Volume

627

Issue

8004

Start / End Page

586 / 593

Location

England

Related Subject Headings

  • Whole Genome Sequencing
  • Reproducibility of Results
  • Open Reading Frames
  • Neoplasm Metastasis
  • Mutation
  • Liver Neoplasms
  • Liver
  • INDEL Mutation
  • Humans
  • High-Throughput Nucleotide Sequencing
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Chen, L., Zhang, C., Xue, R., Liu, M., Bai, J., Bao, J., … Wang, H. (2024). Deep whole-genome analysis of 494 hepatocellular carcinomas. Nature, 627(8004), 586–593. https://doi.org/10.1038/s41586-024-07054-3
Chen, Lei, Chong Zhang, Ruidong Xue, Mo Liu, Jian Bai, Jinxia Bao, Yin Wang, et al. “Deep whole-genome analysis of 494 hepatocellular carcinomas.Nature 627, no. 8004 (March 2024): 586–93. https://doi.org/10.1038/s41586-024-07054-3.
Chen L, Zhang C, Xue R, Liu M, Bai J, Bao J, et al. Deep whole-genome analysis of 494 hepatocellular carcinomas. Nature. 2024 Mar;627(8004):586–93.
Chen, Lei, et al. “Deep whole-genome analysis of 494 hepatocellular carcinomas.Nature, vol. 627, no. 8004, Mar. 2024, pp. 586–93. Pubmed, doi:10.1038/s41586-024-07054-3.
Chen L, Zhang C, Xue R, Liu M, Bai J, Bao J, Wang Y, Jiang N, Li Z, Wang W, Wang R, Zheng B, Yang A, Hu J, Liu K, Shen S, Zhang Y, Bai M, Zhu Y, Yang S, Gao Q, Gu J, Gao D, Wang XW, Nakagawa H, Zhang N, Wu L, Rozen SG, Bai F, Wang H. Deep whole-genome analysis of 494 hepatocellular carcinomas. Nature. 2024 Mar;627(8004):586–593.
Journal cover image

Published In

Nature

DOI

EISSN

1476-4687

Publication Date

March 2024

Volume

627

Issue

8004

Start / End Page

586 / 593

Location

England

Related Subject Headings

  • Whole Genome Sequencing
  • Reproducibility of Results
  • Open Reading Frames
  • Neoplasm Metastasis
  • Mutation
  • Liver Neoplasms
  • Liver
  • INDEL Mutation
  • Humans
  • High-Throughput Nucleotide Sequencing