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PMID: 23788652 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Whole-genome sequencing identifies recurrent mutations in hepatocellular carcinoma.

Genome research ·Vol. 23 ·No. 9 ·2013-09-00 ·Pages 1422-33

Kan Z, Zheng H, Liu X, Li S, Barber TD, Gong Z, Gao H, Hao K, Willard MD, Xu J, Hauptschein R, Rejto PA, Fernandez J, Wang G, Zhang Q, Wang B, Chen R, Wang J, Lee NP, Zhou W, Lin Z, Peng Z, Yi K, Chen S, Li L, Fan X, Yang J, Ye R, Ju J, Wang K, Estrella H, Deng S, Wei P, Qiu M, Wulur IH, Liu J, Ehsani ME, Zhang C, Loboda A, Sung WK, Aggarwal A, Poon RT, Fan ST, Wang J, Hardwick J, Reinhard C, Dai H, Li Y, Luk JM, Mao M

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.

MeSH Terms
Amino Acid Sequence Carcinoma, Hepatocellular/genetics,virology DNA, Viral/genetics Female Genome, Human Hepatitis B virus/genetics Humans Janus Kinase 1/genetics Liver Neoplasms/genetics,virology Male Molecular Sequence Data Mutation STAT Transcription Factors/genetics Sequence Analysis, DNA Tumor Suppressor Protein p53/genetics Virus Integration Wnt Signaling Pathway/genetics beta Catenin/genetics
Chemicals
DNA, Viral STAT Transcription Factors Tumor Suppressor Protein p53 beta Catenin JAK1 protein, human Janus Kinase 1
Authors & Affiliations
50 authors, click to expand affiliations / ORCID
Kan Zhengyan
Pfizer Oncology, San Diego, California 92121, USA.
Zheng Hancheng
Liu Xiao
Li Shuyu
Barber Thomas D
Gong Zhuolin
Gao Huan
Hao Ke
Willard Melinda D
Xu Jiangchun
Hauptschein Robert
Rejto Paul A
Fernandez Julio
Wang Guan
Zhang Qinghui
Wang Bo
Chen Ronghua
Wang Jian
Lee Nikki P
Zhou Wei
Lin Zhao
Peng Zhiyu
Yi Kang
Chen Shengpei
Li Lin
Fan Xiaomei
Yang Jie
Ye Rui
Ju Jia
Wang Kai
Estrella Heather
Deng Shibing
Wei Ping
Qiu Ming
Wulur Isabella H
Liu Jiangang
Ehsani Mariam E
Zhang Chunsheng
Loboda Andrey
Sung Wing Kin
Aggarwal Amit
Poon Ronnie T
Fan Sheung Tat
Wang Jun
Hardwick James
Reinhard Christoph
Dai Hongyue
Li Yingrui
Luk John M
Mao Mao
References (66)
66 references, click to expand
  1. A census of human cancer genes.
    Nat Rev Cancer. 2004 Mar;4(3):177-83 PMID: 14993899
  2. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial.
    Lancet. 2010 Jul 24;376(9737):245-51 PMID: 20609468
  3. NF-κB and STAT3 - key players in liver inflammation and cancer.
    Cell Res. 2011 Jan;21(1):159-68 PMID: 21187858
  4. Clinical significance of high focal adhesion kinase gene copy number and overexpression in invasive breast cancer.
    Breast Cancer Res Treat. 2011 Aug;128(3):647-55 PMID: 20814816
  5. Dickkopfs and Wnt/β-catenin signalling in liver cancer.
    World J Clin Oncol. 2011 Aug 10;2(8):311-25 PMID: 21876852
  6. Assessing the significance of chromosomal aberrations in cancer: methodology and application to glioma.
    Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):20007-12 PMID: 18077431
  7. AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1.
    Nat Genet. 2000 Mar;24(3):245-50 PMID: 10700176
  8. Mutational analysis of JAK1 gene in human hepatocellular carcinoma.
    Neoplasma. 2009;56(2):136-40 PMID: 19239328
  9. Next generation sequencing reveals genetic landscape of hepatocellular carcinomas.
    Cancer Lett. 2013 Nov 1;340(2):247-53 PMID: 23063663
  10. ARID1A mutations in endometriosis-associated ovarian carcinomas.
    N Engl J Med. 2010 Oct 14;363(16):1532-43 PMID: 20942669
  11. Fast and accurate short read alignment with Burrows-Wheeler transform.
    Bioinformatics. 2009 Jul 15;25(14):1754-60 PMID: 19451168
  12. Patterns of somatic mutation in human cancer genomes.
    Nature. 2007 Mar 8;446(7132):153-8 PMID: 17344846
  13. High prevalence of K-ras-2 mutations in hepatocellular carcinomas in workers exposed to vinyl chloride.
    Int Arch Occup Environ Health. 2001 Aug;74(6):405-10 PMID: 11563603
  14. The role of signaling pathways in the development and treatment of hepatocellular carcinoma.
    Oncogene. 2010 Sep 9;29(36):4989-5005 PMID: 20639898
  15. Dissecting specificity in the Janus kinases: the structures of JAK-specific inhibitors complexed to the JAK1 and JAK2 protein tyrosine kinase domains.
    J Mol Biol. 2009 Mar 20;387(1):219-32 PMID: 19361440
  16. High-resolution mapping of copy-number alterations with massively parallel sequencing.
    Nat Methods. 2009 Jan;6(1):99-103 PMID: 19043412
  17. Liver stem cells and hepatocellular carcinoma.
    Hepatology. 2009 Jan;49(1):318-29 PMID: 19111019
  18. HDPR1, a novel inhibitor of the WNT/beta-catenin signaling, is frequently downregulated in hepatocellular carcinoma: involvement of methylation-mediated gene silencing.
    Oncogene. 2005 Feb 24;24(9):1607-14 PMID: 15580286
  19. Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling.
    Nature. 2011 Jul 04;476(7360):293-7 PMID: 21727895
  20. The aflatoxin-induced TP53 mutation at codon 249 (R249S): biomarker of exposure, early detection and target for therapy.
    Cancer Lett. 2009 Dec 1;286(1):29-37 PMID: 19376640
  21. Genomic sequencing of colorectal adenocarcinomas identifies a recurrent VTI1A-TCF7L2 fusion.
    Nat Genet. 2011 Sep 04;43(10):964-968 PMID: 21892161
  22. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial.
    Lancet. 2010 Jul 24;376(9737):235-44 PMID: 20609467
  23. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro.
    Breast Cancer Res. 2009;11(5):R77 PMID: 19874578
  24. Identification of genomic indels and structural variations using split reads.
    BMC Genomics. 2011 Jul 25;12:375 PMID: 21787423
  25. Molecular signatures database (MSigDB) 3.0.
    Bioinformatics. 2011 Jun 15;27(12):1739-40 PMID: 21546393
  26. A tumor suppressive coactivator complex of p53 containing ASC-2 and histone H3-lysine-4 methyltransferase MLL3 or its paralogue MLL4.
    Proc Natl Acad Sci U S A. 2009 May 26;106(21):8513-8 PMID: 19433796
  27. SOAP2: an improved ultrafast tool for short read alignment.
    Bioinformatics. 2009 Aug 1;25(15):1966-7 PMID: 19497933
  28. Inactivating mutations of the chromatin remodeling gene ARID2 in hepatocellular carcinoma.
    Nat Genet. 2011 Aug 07;43(9):828-9 PMID: 21822264
  29. Identification of a therapeutic strategy targeting amplified FGF19 in liver cancer by Oncogenomic screening.
    Cancer Cell. 2011 Mar 8;19(3):347-58 PMID: 21397858
  30. Somatically acquired JAK1 mutations in adult acute lymphoblastic leukemia.
    J Exp Med. 2008 Apr 14;205(4):751-8 PMID: 18362173
  31. Global cancer statistics.
    CA Cancer J Clin. 2011 Mar-Apr;61(2):69-90 PMID: 21296855
  32. Activation of the beta-catenin gene in primary hepatocellular carcinomas by somatic alterations involving exon 3.
    Cancer Res. 1998 Jun 15;58(12):2524-7 PMID: 9635572
  33. Somatic mutations affect key pathways in lung adenocarcinoma.
    Nature. 2008 Oct 23;455(7216):1069-75 PMID: 18948947
  34. DNA damage and polyploidization.
    Adv Exp Med Biol. 2010;676:57-71 PMID: 20687469
  35. DAVID: Database for Annotation, Visualization, and Integrated Discovery.
    Genome Biol. 2003;4(5):P3 PMID: 12734009
  36. Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma.
    Cancer Res. 2009 Sep 15;69(18):7385-92 PMID: 19723656
  37. Predictive genes in adjacent normal tissue are preferentially altered by sCNV during tumorigenesis in liver cancer and may rate limiting.
    PLoS One. 2011;6(7):e20090 PMID: 21750698
  38. Wnt signalling and its impact on development and cancer.
    Nat Rev Cancer. 2008 May;8(5):387-98 PMID: 18432252
  39. Cancer genomics: from discovery science to personalized medicine.
    Nat Med. 2011 Mar;17(3):297-303 PMID: 21383744
  40. Somatic mutations in the chromatin remodeling gene ARID1A occur in several tumor types.
    Hum Mutat. 2012 Jan;33(1):100-3 PMID: 22009941
  41. COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer.
    Nucleic Acids Res. 2011 Jan;39(Database issue):D945-50 PMID: 20952405
  42. Ruxolitinib.
    Nat Rev Drug Discov. 2012 Feb 01;11(2):103-4 PMID: 22293561
  43. High-resolution characterization of a hepatocellular carcinoma genome.
    Nat Genet. 2011 May;43(5):464-9 PMID: 21499249
  44. Identifying cancer driver genes in tumor genome sequencing studies.
    Bioinformatics. 2011 Jan 15;27(2):175-81 PMID: 21169372
  45. More powerful procedures for multiple significance testing.
    Stat Med. 1990 Jul;9(7):811-8 PMID: 2218183
  46. Frequent in-frame somatic deletions activate gp130 in inflammatory hepatocellular tumours.
    Nature. 2009 Jan 8;457(7226):200-4 PMID: 19020503
  47. The pseudokinase domain is required for suppression of basal activity of Jak2 and Jak3 tyrosine kinases and for cytokine-inducible activation of signal transduction.
    J Biol Chem. 2002 Dec 6;277(49):47954-63 PMID: 12351625
  48. Janus kinase inhibitors for the treatment of myeloproliferative neoplasias and beyond.
    Nat Rev Drug Discov. 2011 Feb;10(2):127-40 PMID: 21283107
  49. Genome-wide survey of recurrent HBV integration in hepatocellular carcinoma.
    Nat Genet. 2012 May 27;44(7):765-9 PMID: 22634754
  50. Initial genome sequencing and analysis of multiple myeloma.
    Nature. 2011 Mar 24;471(7339):467-72 PMID: 21430775
  51. GNAS-activating mutations define a rare subgroup of inflammatory liver tumors characterized by STAT3 activation.
    J Hepatol. 2012 Jan;56(1):184-91 PMID: 21835143
  52. Somatic mutations activating STAT3 in human inflammatory hepatocellular adenomas.
    J Exp Med. 2011 Jul 4;208(7):1359-66 PMID: 21690253
  53. Integrative genomics viewer.
    Nat Biotechnol. 2011 Jan;29(1):24-6 PMID: 21221095
  54. Geographic variation of p53 mutational profile in nonmalignant human liver.
    Science. 1994 May 27;264(5163):1317-9 PMID: 8191284
  55. Cancer gene discovery in hepatocellular carcinoma.
    J Hepatol. 2010 Jun;52(6):921-9 PMID: 20385424
  56. Focal adhesion kinase (FAK) gene amplification and its clinical implications in gastric cancer.
    Hum Pathol. 2010 Dec;41(12):1664-73 PMID: 20869748
  57. Characterization of BMS-911543, a functionally selective small-molecule inhibitor of JAK2.
    Leukemia. 2012 Feb;26(2):280-8 PMID: 22015772
  58. The global health burden of infection-associated cancers in the year 2002.
    Int J Cancer. 2006 Jun 15;118(12):3030-44 PMID: 16404738
  59. Molecular basis of human Usher syndrome: deciphering the meshes of the Usher protein network provides insights into the pathomechanisms of the Usher disease.
    Exp Eye Res. 2006 Jul;83(1):97-119 PMID: 16545802
  60. Exome sequencing identifies frequent mutation of ARID1A in molecular subtypes of gastric cancer.
    Nat Genet. 2011 Oct 30;43(12):1219-23 PMID: 22037554
  61. Secreted antagonists of the Wnt signalling pathway.
    J Cell Sci. 2003 Jul 1;116(Pt 13):2627-34 PMID: 12775774
  62. Acute lymphoblastic leukemia-associated JAK1 mutants activate the Janus kinase/STAT pathway via interleukin-9 receptor alpha homodimers.
    J Biol Chem. 2009 Mar 13;284(11):6773-81 PMID: 19139102
  63. Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms.
    Blood. 2010 Apr 15;115(15):3109-17 PMID: 20130243
  64. Oncogenic JAK1 and JAK2-activating mutations resistant to ATP-competitive inhibitors.
    Haematologica. 2011 Jun;96(6):845-53 PMID: 21393331
  65. Mechanisms of HBV-related hepatocarcinogenesis.
    J Hepatol. 2010 Apr;52(4):594-604 PMID: 20185200
  66. Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma.
    Nature. 2011 Jan 27;469(7331):539-42 PMID: 21248752
Article Info
Journal
Genome research
Abbr.
Genome Res
ISSN
1549-5469
DOI
10.1101/gr.154492.113
Published
2013-09-00
Epub
2013-00-20
Pages
1422-33
Language
English
Region
United States
NLM ID
9518021
PMCID
PMC3759719
Subset
IM
External Links
PubMed source DOI: 10.1101/gr.154492.113 PMC Full Text View journal details
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