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Genomic landscape of hepatocarcinogenesis

Journal of Human Genetics volume 66, pages 845–851 (2021)Cite this article

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Abstract

Hepatocellular carcinoma (HCC) is a global health issue and the fourth leading cause of cancer deaths worldwide. Large-scale HCC genome sequencing analyses have identified core drivers (TERT, TP53, and CTNNB1/AXIN1) as initial molecular events, and other low-frequent drivers that include therapeutically targetable ones. The recent genetic analysis uncovered a distinctive driver gene landscape in precancerous lesions, arguing a discontinuous process at early HCC development. In advanced tumors, intra-tumoral heterogeneity through clonal evolution processes is common, and it displays clear geographic segregation genetically and epigenetically. Diverse epidemiological risk factors for HCC mirrors heterogeneous mutational processes among patient cohorts with distinctive ethnicity, environmental exposures, and lifestyles. The genetic information of individual tumors has been utilized for optimizing treatments, early diagnosis, and monitoring recurrence. It will expand the opportunity for screening high-risk populations, thereby preventing hepatocarcinogenesis in the near future.

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References

  1. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet. 2003;362:1907–17.

    Article  Google Scholar 

  2. Shibata T, Aburatani H. Exploration of liver cancer genomes. Nat Rev Gastroenterol Hepatol. 2014;11:340–9.

    Article  CAS  Google Scholar 

  3. Totoki Y, Tatsuno K, Covington KR, et al. Trans-ancestry mutational landscape of hepatocellular carcinoma genomes. Nat Genet. 2014;46:1267–73.

    Article  CAS  Google Scholar 

  4. Schulze K, Imbeaud S, Letouzé E, et al. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat Genet. 2015;47:505–11.

    Article  CAS  Google Scholar 

  5. Fujimoto A, Furuta M, Totoki Y, et al. Whole-genome mutational landscape and characterization of noncoding and structural mutations in liver cancer. Nat Genet. 2016;48:500–9.

    Article  CAS  Google Scholar 

  6. Cancer Genome Atlas Research Network. Comprehensive and integrative genomic characterization of hepatocellular carcinoma. Cell. 2017;169:1327–41.

    Article  Google Scholar 

  7. Nault JC, Mallet M, Pilati C, et al. High frequency of telomerase reverse-transcriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions. Nat Commun. 2013;4:2218.

    Article  Google Scholar 

  8. Midorikawa Y, Yamamoto S, Tatsuno K, et al. Accumulation of molecular aberrations distinctive to hepatocellular carcinoma progression. Cancer Res. 2020;80:3810–9.

    Article  CAS  Google Scholar 

  9. St Pierre R, Kadoch C. Mammalian SWI/SNF complexes in cancer: emerging therapeutic opportunities. Curr Opin Genet Dev. 2017;42:56–67.

    Article  CAS  Google Scholar 

  10. Sun X, Wang SC, Wei Y, et al. Arid1a has context-dependent oncogenic and tumor suppressor functions in liver cancer. Cancer Cell. 2017;32:574–89.

    Article  CAS  Google Scholar 

  11. Ogiwara H, Takahashi K, Sasaki M, et al. Targeting the vulnerability of glutathione metabolism in ARID1A-deficient cancers. Cancer Cell. 2019;35:177–90.

    Article  CAS  Google Scholar 

  12. Sankar TS, Wastuwidyaningtyas BD, Dong Y, et al. The nature of mutations induced by replication–transcription collisions. Nature. 2016;535:178–81.

    Article  CAS  Google Scholar 

  13. Zhu M, Lu T, Jia Y, et al. Somatic mutations increase hepatic clonal fitness and regeneration in chronic liver disease. Cell. 2019;177:608–21.

    Article  CAS  Google Scholar 

  14. Kim SK, Takeda H, Takai A, et al. Comprehensive analysis of genetic aberrations linked to tumorigenesis in regenerative nodules of liver cirrhosis. J Gastroenterol. 2019;54:628–40.

    Article  CAS  Google Scholar 

  15. Brunner SF, Roberts ND, Wylie LA, et al. Somatic mutations and clonal dynamics in healthy and cirrhotic human liver. Nature. 2019;574:538–42.

    Article  CAS  Google Scholar 

  16. Alexandrov LB, Kim J, Haradhvala NJ, et al. The repertoire of mutational signatures in human cancer. Nature. 2020;578:94–101.

    Article  CAS  Google Scholar 

  17. Ng AWT, Poon SL, Huang MN, et al. Aristolochic acids and their derivatives are widely implicated in liver cancers in Taiwan and throughout Asia. Sci Transl Med. 2017;9:eaan6446.

    Article  Google Scholar 

  18. Lu ZN, Luo Q, Zhao LN, et al. The mutational features of aristolochic acid-induced mouse and human liver cancers. Hepatology. 2020;71:929–42.

    Article  CAS  Google Scholar 

  19. Hama N, Totoki Y, Miura F, et al. Epigenetic landscape influences the liver cancer genome architecture. Nat Commun. 2018;9:1643.

    Article  Google Scholar 

  20. Sung WK, Zheng H, Li S, et al. Genome-wide survey of recurrent HBV integration in hepatocellular carcinoma. Nat Genet. 2012;44:765–9.

    Article  CAS  Google Scholar 

  21. Zhao LH, Liu X, Yan HX, et al. Genomic and oncogenic preference of HBV integration in hepatocellular carcinoma. Nat Commun. 2016;7:12992.

    Article  CAS  Google Scholar 

  22. Furuta M, Tanaka H, Shiraishi Y, et al. Characterization of HBV integration patterns and timing in liver cancer and HBV-infected livers. Oncotarget. 2018;9:25075–88.

    Article  Google Scholar 

  23. Nault JC, Datta S, Imbeaud S, et al. Recurrent AAV2-related insertional mutagenesis in human hepatocellular carcinomas. Nat Genet. 2015;47:1187–93.

    Article  CAS  Google Scholar 

  24. Park KJ, Lee J, Park JH, et al. Adeno-associated virus 2-mediated hepatocellular carcinoma is very rare in Korean patients. Ann Lab Med. 2016;36:469–74.

    Article  Google Scholar 

  25. Tatsuno K, Midorikawa Y, Takayama T, et al. Impact of AAV2 and hepatitis B virus integration into genome on development of hepatocellular carcinoma in patients with prior hepatitis B virus infection. Clin Cancer Res. 2019;25:6217–27.

    Article  CAS  Google Scholar 

  26. La Bella T, Imbeaud S, Peneau C, et al. Adeno-associated virus in the liver: natural history and consequences in tumour development. Gut. 2020;69:737–47.

    Article  Google Scholar 

  27. Kudo M. Early hepatocellular carcinoma: definition and diagnosis. Liver Cancer. 2013;2:69–72.

    Article  CAS  Google Scholar 

  28. Takeda H, Takai A, Kumagai K, et al. Multiregional whole-genome sequencing of hepatocellular carcinoma with nodule-in-nodule appearance reveals stepwise cancer evolution. J Pathol. 2020;252:398–410.

    Article  CAS  Google Scholar 

  29. Zhai W, Lim TK, Zhang T, et al. The spatial organization of intra-tumour heterogeneity and evolutionary trajectories of metastases in hepatocellular carcinoma. Nat Commun. 2017;8:4565.

    Article  CAS  Google Scholar 

  30. Ding X, He M, Chan AWH, et al. Genomic and epigenomic features of primary and recurrent hepatocellular carcinomas. Gastroenterology. 2019;157:1630–45.e6.

    Article  CAS  Google Scholar 

  31. Furuta M, Ueno M, Fujimoto A, et al. Whole genome sequencing discriminates hepatocellular carcinoma with intrahepatic metastasis from multi-centric tumors. J Hepatol. 2017;66:363–73.

    Article  CAS  Google Scholar 

  32. Cai Z, Chen G, Zeng Y, et al. Comprehensive liquid profiling of circulating tumor DNA and protein biomarkers in long-term follow-up patients with hepatocellular carcinoma. Clin Cancer Res. 2019;25:5284–94.

    Article  CAS  Google Scholar 

  33. Qu C, Wang Y, Wang P, et al. Detection of early-stage hepatocellular carcinoma in asymptomatic HBsAg-seropositive individuals by liquid biopsy. Proc Natl Acad Sci USA. 2019;116:6308–12.

    Article  CAS  Google Scholar 

  34. Hadi K, Yao X, Behr JM, et al. Distinct classes of complex structural variation uncovered across thousands of cancer genome graphs. Cell. 2020;183:197–210.

    Article  CAS  Google Scholar 

  35. Shibata T, Arai Y, Totoki Y. Molecular genomic landscapes of hepatobiliary cancer. Cancer Sci. 2018;109:1282–91.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported in part by the Practical Research for Innovative Cancer Control from the Japan Agency for Medical Research and Development (AMED, JP20ck0106547h0001), National Cancer Center Research and Development Funds (2020-A-7).

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  1. Laboratory of Molecular Medicine, The Institute of Medical Sciences, The University of Tokyo, Tokyo, Japan

    Tatsuhiro Shibata

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Correspondence to Tatsuhiro Shibata.

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Shibata, T. Genomic landscape of hepatocarcinogenesis. J Hum Genet 66, 845–851 (2021). https://doi.org/10.1038/s10038-021-00928-8

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