Whole-genome sequencing identifies recurrent mutations in hepatocellular carcinoma (original) (raw)

  1. Hancheng Zheng2,13,
  2. Xiao Liu2,3,13,
  3. Shuyu Li4,13,
  4. Thomas D. Barber4,
  5. Zhuolin Gong2,
  6. Huan Gao2,
  7. Ke Hao5,
  8. Melinda D. Willard4,
  9. Jiangchun Xu1,
  10. Robert Hauptschein1,
  11. Paul A. Rejto1,
  12. Julio Fernandez1,
  13. Guan Wang2,
  14. Qinghui Zhang2,
  15. Bo Wang2,
  16. Ronghua Chen5,
  17. Jian Wang4,
  18. Nikki P. Lee6,
  19. Wei Zhou5,
  20. Zhao Lin2,
  21. Zhiyu Peng2,
  22. Kang Yi2,
  23. Shengpei Chen2,
  24. Lin Li2,
  25. Xiaomei Fan2,
  26. Jie Yang2,
  27. Rui Ye2,
  28. Jia Ju2,
  29. Kai Wang1,
  30. Heather Estrella1,
  31. Shibing Deng1,
  32. Ping Wei1,
  33. Ming Qiu1,
  34. Isabella H. Wulur4,
  35. Jiangang Liu4,
  36. Mariam E. Ehsani4,
  37. Chunsheng Zhang5,
  38. Andrey Loboda5,
  39. Wing Kin Sung6,7,
  40. Amit Aggarwal4,
  41. Ronnie T. Poon6,
  42. Sheung Tat Fan6,
  43. Jun Wang2,3,8,9,
  44. James Hardwick5,10,
  45. Christoph Reinhard4,
  46. Hongyue Dai5,
  47. Yingrui Li2,14,
  48. John M. Luk6,11,12,14 and
  49. Mao Mao1,10,14
  50. 1Pfizer Oncology, San Diego, California 92121, USA;
  51. 2BGI-Shenzhen, Shenzhen 518083, China;
  52. 3Department of Biology, University of Copenhagen, Copenhagen, Denmark;
  53. 4Eli Lilly and Company, Indianapolis, Indiana 46285, USA;
  54. 5Merck Research Laboratories, Boston, Massachusetts 02115, USA;
  55. 6Department of Surgery, University of Hong Kong, Hong Kong, China;
  56. 7School of Computing, National University of Singapore, Singapore 117417;
  57. 8The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark;
  58. 9King Abdulaziz University, Jeddah, Saudi Arabia;
  59. 10Asian Cancer Research Group, Inc., Wilmington, Delaware 19808, USA;
  60. 11Departments of Pharmacology and Surgery, National University of Singapore, Singapore 117597;
  61. 12Institute of Molecular and Cell Biology, A*STAR, Singapore 138673
  62. ↵13 These authors contributed equally to this work.

Abstract

Hepatocellular carcinoma (HCC) is one of the most deadly cancers worldwide and has no effective treatment, yet the molecular basis of hepatocarcinogenesis remains largely unknown. Here we report findings from a whole-genome sequencing (WGS) study of 88 matched HCC tumor/normal pairs, 81 of which are Hepatitis B virus (HBV) positive, seeking to identify genetically altered genes and pathways implicated in HBV-associated HCC. We find beta-catenin to be the most frequently mutated oncogene (15.9%) and TP53 the most frequently mutated tumor suppressor (35.2%). The Wnt/beta-catenin and JAK/STAT pathways, altered in 62.5% and 45.5% of cases, respectively, are likely to act as two major oncogenic drivers in HCC. This study also identifies several prevalent and potentially actionable mutations, including activating mutations of Janus kinase 1 (JAK1), in 9.1% of patients and provides a path toward therapeutic intervention of the disease.

Footnotes

This article, published in Genome Research, is available under a Creative Commons License (Attribution-NonCommercial 3.0 Unported), as described at http://creativecommons.org/licenses/by-nc/3.0/.