Deep whole-genome analysis of 494 hepatocellular carcinomas.

Autor: Chen L; National Center for Liver Cancer/Eastern Hepatobiliary Surgery Hospital, Shanghai, China. chenlei@smmu.edu.cn., Zhang C; Biomedical Pioneering Innovation Center (BIOPIC), Beijing Advanced Innovation Center for Genomics (ICG), School of Life Sciences, Peking University, Beijing, China., Xue R; Peking University-Yunnan Baiyao International Medical Research Center, International Cancer Institute, Department of Medical Bioinformatics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.; Translational Cancer Research Center, Peking University First Hospital, Beijing, China., Liu M; Centre for Computational Biology and Programme in Cancer & Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore., Bai J; Berry Oncology Corporation, Beijing, China., Bao J; Model Animal Research Center, Medical School, Nanjing University, Nanjing, China., Wang Y; Berry Oncology Corporation, Beijing, China., Jiang N; Centre for Computational Biology and Programme in Cancer & Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore., Li Z; National Center for Liver Cancer/Eastern Hepatobiliary Surgery Hospital, Shanghai, China., Wang W; The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Shanghai, China., Wang R; Berry Oncology Corporation, Beijing, China., Zheng B; National Center for Liver Cancer/Eastern Hepatobiliary Surgery Hospital, Shanghai, China.; The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Shanghai, China., Yang A; Berry Oncology Corporation, Beijing, China., Hu J; National Center for Liver Cancer/Eastern Hepatobiliary Surgery Hospital, Shanghai, China.; The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Shanghai, China., Liu K; Berry Oncology Corporation, Beijing, China., Shen S; National Center for Liver Cancer/Eastern Hepatobiliary Surgery Hospital, Shanghai, China.; The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Shanghai, China., Zhang Y; National Center for Liver Cancer/Eastern Hepatobiliary Surgery Hospital, Shanghai, China., Bai M; National Center for Liver Cancer/Eastern Hepatobiliary Surgery Hospital, Shanghai, China., Wang Y; Berry Oncology Corporation, Beijing, China., Zhu Y; National Center for Liver Cancer/Eastern Hepatobiliary Surgery Hospital, Shanghai, China.; The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Shanghai, China., Yang S; National Center for Liver Cancer/Eastern Hepatobiliary Surgery Hospital, Shanghai, China.; The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Shanghai, China., Gao Q; Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China., Gu J; MOE Key Laboratory for Bioinformatics, Department of Automation, Tsinghua University, Beijing, China., Gao D; State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, CAS, Shanghai, China., Wang XW; Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA., Nakagawa H; Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan., Zhang N; Peking University-Yunnan Baiyao International Medical Research Center, International Cancer Institute, Department of Medical Bioinformatics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.; Translational Cancer Research Center, Peking University First Hospital, Beijing, China., Wu L; Berry Oncology Corporation, Beijing, China. wulin@berryoncology.com., Rozen SG; Centre for Computational Biology and Programme in Cancer & Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore. steve.rozen@duke-nus.edu.sg., Bai F; Biomedical Pioneering Innovation Center (BIOPIC), Beijing Advanced Innovation Center for Genomics (ICG), School of Life Sciences, Peking University, Beijing, China. fbai@pku.edu.cn., Wang H; National Center for Liver Cancer/Eastern Hepatobiliary Surgery Hospital, Shanghai, China. hywangk@vip.sina.com.
Jazyk: angličtina
Zdroj: Nature [Nature] 2024 Mar; Vol. 627 (8004), pp. 586-593. Date of Electronic Publication: 2024 Feb 14.
DOI: 10.1038/s41586-024-07054-3
Abstrakt: 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.
(© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
Externí odkaz: