Deep whole-genome analysis of 494 hepatocellular carcinomas
Abstract
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, reg…
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Human HCCs with CTNNB1 and ARID2 mutations from two independent studies also showed up-regulation of many of the same WNT pathway genes (NOTUM, AQP9, TBX3, ABCB11, GLUL) as observed in mouse models.
“Notably, human HCCs with CTNNB1 and ARID2 mutations from two independent studies (25, 35) also showed up-regulation of many of the same WNT pathway genes (NOTUM, AQP9, TBX3, ABCB11, GLUL) as observed in our mouse models (fig. S6B and table S4).”
From The origin of hepatocellular carcinoma depends on metabolic zonation (2026) · cites this paper as [35]
No citation lists for this paper
No citation lists for this paper yet — checked again daily.
References 59 · Cited by 148
- Authors
- 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., Wang, Y., Zhu, Y., Yang, S., Gao, Q., Gu, J., Gao, D., Wang, X. W., Nakagawa, H., Zhang, N., Wu, L., Rozen, S. G., Bai, F., & Wang, H.
- Affiliations
- Eastern Hepatobiliary Surgery Hospital (CN)
- Peking University (CN)
- National University of Singapore (SG)
- Berry Oncology (China) (CN)
- Model Animal Research Center (CN)
- Fudan University (CN)
- Tsinghua University (CN)
- Chinese Academy of Sciences (CN)
- National Cancer Institute (US)
- RIKEN Center for Integrative Medical Sciences (JP)
- Corresponding author
- Chen, Lei
- Wu, Lin
- Bai, Fan
- Wang, Hongyang
- ORCID
- Venue
- Nature
- Published
- 2024-02-14
- Volume
- 627
- Issue
- 8004
- Pages
- 586-593
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W4391824116
- Cited by
- 148
- References
- 59
- Citations by year
- 2026: 51 · 2025: 69 · 2024: 28
- FWCI
- 29.52
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Japan Society for the Promotion of Science (23K24324)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Epidemiology › Hepatitis B Virus Studies
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Keywords
- hepatocellular carcinoma, hepatitis B virus, mutational signatures, non-coding mutations, driver mutations, extrachromosomal circular DNA, HBV DNA integration, chromothripsis, chromoplexy, kataegis, subclonal evolution, hepatocarcinogenesis, hepatic metabolism, fibrinogen alpha chain, metastasis, Chinese patients
- MeSH terms
- Chromothripsis, Whole Genome Sequencing, East Asian People, China, DNA, Circular, Hepatitis B virus, Carcinoma, Hepatocellular, Humans, Liver, Liver Neoplasms, Mutation, Neoplasm Metastasis, Reproducibility of Results, Genome, Human, Open Reading Frames, Disease Progression, Evolution, Molecular, Aristolochic Acids, INDEL Mutation, High-Throughput Nucleotide Sequencing, Carcinogenesis
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
