Gastroenterology

Gastroenterology

Volume 156, Issue 2, January 2019, Pages 492-509
Gastroenterology

Review
Genomic Medicine and Implications for Hepatocellular Carcinoma Prevention and Therapy

https://doi.org/10.1053/j.gastro.2018.11.001Get rights and content

The pathogenesis of hepatocellular carcinoma (HCC) is poorly understood, but recent advances in genomics have increased our understanding of the mechanisms by which hepatitis B virus, hepatitis C virus, alcohol, fatty liver disease, and other environmental factors, such as aflatoxin, cause liver cancer. Genetic analyses of liver tissues from patients have provided important information about tumor initiation and progression. Findings from these studies can potentially be used to individualize the management of HCC. In addition to sorafenib, other multi-kinase inhibitors have been approved recently for treatment of HCC, and the preliminary success of immunotherapy has raised hopes. Continued progress in genomic medicine could improve classification of HCCs based on their molecular features and lead to new treatments for patients with liver cancer.

Section snippets

Genetics

Over the past decade, the study of cancer has shifted from evaluation of variants of individual genes and pathways to analyses of gene expression patterns and epigenetic profiles of tumor tissues and cells. Advances in next-generation sequencing and computational data analyses can be credited for this shift. The genetic events that contribute to HCC initiation and progression can be classified as genomic (somatic mutations and genome structure changes, such as gene fusions or copy number

Somatic Genomic Events

Somatic mutations occur in somatic (non-germ) cells and are therefore not heritable. When these mutations occur in proto-oncogenes or tumor suppressor genes or in genes involved in regulatory pathways, they can lead to cell transformation and tumorigenesis. Whole-exome and whole-genome sequencing studies have identified mutations that contribute to development of HCC.9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 The well-characterized mutations in HCCs are in CTNNB1 (which encodes β-catenin), TP53,

Telomerase Activation

Hepatocytes become transformed and form malignancies via a series of genetic and epigenetic alterations leading to genome diversification79 (Figure 2). The specific mechanisms of tumorigenesis vary among patients with vs without cirrhosis, among patients with different liver diseases, and in patients exposed to different carcinogens. In patients with chronic hepatitis, non-alcoholic steatohepatitis, or alcoholic liver disease, persistent liver injury leads to cell proliferation in response to

Interactions of Genome Alterations

Interactions among gene mutations, changes in transcription, alterations in epigenetic regulation, environmental factors, and histologic features should all be considered in classification of HCCs.79 Whole-exome and whole-genome sequence analyses of HCCs identified 4 to 6 mutations in oncogenes per tumor; associations and exclusions among these mutations indicate redundancy and/or cooperation between factors in overlapping signaling pathways.9, 10, 15, 17, 19 Mutations occur in groups of genes

Features of Mixed Hepatocholangiocarcinoma Tumors

The genetic features of cholangiocarcinomas differ from those of HCCs in that cholangiocarcinomas have frequent mutations in KRAS, BRAF, BAP1, SMAD4, IDH1, and IDH2, as well as fusion of FGFR2, ROS1, and PRKACA genes, but few TERT promoter mutations.135, 136, 137 However, a continuum seems to exist among cholangiocarcinoma, mixed hepatocholangiocarcinoma, and HCCs with stem cell features, indicating that similar early genetic alterations in different cell types results in different histologic

Personalized Medicine

The goal of personalized medicine is select specific treatments for each individual tumor based on its genotype or other features. This idea is not novel but is becoming a practical reality. Success stories in precision medicine include the use of imatinib mesylate for treatment of chronic myelogenous leukemia,142 BRAF inhibitors for treatment of melanoma with the BRAF V600E mutation,143 tyrosine kinase inhibitors, such as erlotinib for lung adenocarcinomas with alterations in the epidermal

Immunotherapy

The combination of the immune-tolerant microenvironment of the liver, ability of HCV and HBV to evade the immune response, and the immune-modulatory effects of the tumor allow for growth and progression of HCC. Hence, strategies to reactivate anti-tumor immunity can be used to prevent or treat HCC. Nivolumab was recently given accelerated approval for treatment of advanced liver cancer, based on promising results from a phase 2 trial (Checkmate-040).161 Approximately 20% of the patients had

Future Directions

Recent advances in genetic, genomic, and proteomic analyses have increased our understanding of HCC pathogenesis and our ability to classify tumors based on genetic and histologic features. We are learning more about the specific oncogenic effects of HBV, HCV, alcohol, fatty liver disease, and environmental factors, such as aflatoxin and aristolochic acid. We have been identifying genetic alterations that contribute to liver carcinogenesis, learning the sequence of acquisition of these

Acknowledgments

Author contributions: All authors made substantial contributions to conception and design of the review. All authors participated in drafting the article or revising it critically for important intellectual content. LRR and JZR gave final approval of the version to be submitted and any revised version.

References (162)

  • D. Cougot et al.

    The hepatitis B virus X protein functionally interacts with CREB-binding protein/p300 in the regulation of CREB-mediated transcription

    J Biol Chem

    (2007)
  • S. Bandiera et al.

    miR-122–A key factor and therapeutic target in liver disease

    J Hepatol

    (2015)
  • X.-J. Lin et al.

    A serum microRNA classifier for early detection of hepatocellular carcinoma: a multicentre, retrospective, longitudinal biomarker identification study with a nested case-control study

    Lancet Oncol

    (2015)
  • F.P. Marchese et al.

    A long noncoding RNA regulates sister chromatid cohesion

    Mol Cell

    (2016)
  • Y. Du et al.

    Elevation of highly up-regulated in liver cancer (HULC) by hepatitis B virus X protein promotes hepatoma cell proliferation via down-regulating p18

    J Biol Chem

    (2012)
  • C.-C. Lau et al.

    Viral-human chimeric transcript predisposes risk to liver cancer development and progression

    Cancer Cell

    (2014)
  • M. Lawrence et al.

    Lateral thinking: how histone modifications regulate gene expression

    Trends Genet

    (2016)
  • C. He et al.

    High expression of trimethylated histone H3 lysine 4 is associated with poor prognosis in hepatocellular carcinoma

    Hum Pathol

    (2012)
  • J. Zucman-Rossi et al.

    Genetic landscape and biomarkers of hepatocellular carcinoma

    Gastroenterology

    (2015)
  • C. Günes et al.

    The role of telomeres in stem cells and cancer

    Cell

    (2013)
  • S. Torrecilla et al.

    Trunk mutational events present minimal intra- and inter-tumoral heterogeneity in hepatocellular carcinoma

    J Hepatol

    (2017)
  • J.-C. Nault et al.

    Hepatocellular benign tumors-from molecular classification to personalized clinical care

    Gastroenterology

    (2013)
  • J.-C. Nault et al.

    Molecular classification of hepatocellular adenoma associates with risk factors, bleeding, and malignant transformation

    Gastroenterology

    (2017)
  • C. Pilati et al.

    Genomic profiling of hepatocellular adenomas reveals recurrent FRK-activating mutations and the mechanisms of malignant transformation

    Cancer Cell

    (2014)
  • L.B. Alexandrov et al.

    Deciphering signatures of mutational processes operative in human cancer

    Cell Rep

    (2013)
  • C. Neuveut et al.

    Mechanisms of HBV-related hepatocarcinogenesis

    J Hepatol

    (2010)
  • J. Ferlay et al.

    Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012

    Int J Cancer

    (2014)
  • W. Chen et al.

    Cancer statistics in China, 2015

    CA Cancer J Clin

    (2016)
  • S.-W. Yi et al.

    Risk factors for hepatocellular carcinoma by age, sex, and liver disorder status: a prospective cohort study in Korea

    Cancer

    (2018)
  • A. Gomaa et al.

    Hepatitis C infection in Egypt: prevalence, impact and management strategies

    Hepat Med

    (2017)
  • A.B. Ryerson et al.

    Annual Report to the Nation on the Status of Cancer, 1975-2012, featuring the increasing incidence of liver cancer

    Cancer

    (2016)
  • T. Umemura et al.

    Epidemiology of hepatocellular carcinoma in Japan

    J Gastroenterol

    (2009)
  • A. Fujimoto et al.

    Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators

    Nat Genet

    (2012)
  • C. Guichard et al.

    Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma

    Nat Genet

    (2012)
  • S.P. Cleary et al.

    Identification of driver genes in hepatocellular carcinoma by exome sequencing

    Hepatology

    (2013)
  • Z. Kan et al.

    Whole-genome sequencing identifies recurrent mutations in hepatocellular carcinoma

    Genome Res

    (2013)
  • S.-M. Ahn et al.

    Genomic portrait of resectable hepatocellular carcinomas: implications of RB1 and FGF19 aberrations for patient stratification

    Hepatology

    (2014)
  • S. Jhunjhunwala et al.

    Diverse modes of genomic alteration in hepatocellular carcinoma

    Genome Biol

    (2014)
  • Y. Totoki et al.

    Trans-ancestry mutational landscape of hepatocellular carcinoma genomes

    Nat Genet

    (2014)
  • Y. Shiraishi et al.

    Integrated analysis of whole genome and transcriptome sequencing reveals diverse transcriptomic aberrations driven by somatic genomic changes in liver cancers

    PLoS One

    (2014)
  • K. Schulze et al.

    Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets

    Nat Genet

    (2015)
  • A. Fujimoto et al.

    Whole-genome mutational landscape and characterization of noncoding and structural mutations in liver cancer

    Nat Genet

    (2016)

  • Comprehensive and integrative genomic characterization of hepatocellular carcinoma

    Cell

    (2017)
  • J.C. Nault et al.

    High frequency of telomerase reverse-transcriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions

    Nat Commun

    (2013)
  • J.C. Nault et al.

    Telomerase reverse transcriptase promoter mutation is an early somatic genetic alteration in the transformation of premalignant nodules in hepatocellular carcinoma on cirrhosis

    Hepatology

    (2014)
  • F. Pezzuto et al.

    Tumor specific mutations in TERT promoter and CTNNB1 gene in hepatitis B and hepatitis C related hepatocellular carcinoma

    Oncotarget

    (2016)
  • L.-H. Zhao et al.

    Genomic and oncogenic preference of HBV integration in hepatocellular carcinoma

    Nat Commun

    (2016)
  • B. Tang et al.

    Human telomerase reverse transcriptase (hTERT) promotes gastric cancer invasion through cooperating with c-Myc to upregulate heparanase expression

    Oncotarget

    (2015)
  • J.-I. Park et al.

    Telomerase modulates Wnt signalling by association with target gene chromatin

    Nature

    (2009)
  • A. Ghosh et al.

    Telomerase directly regulates NF-κB-dependent transcription

    Nat Cell Biol

    (2012)

    • Cited by (131)

    • How CLSPN could demystify its prognostic value and potential molecular mechanism for hepatocellular carcinoma: A crosstalk study

      2024, Computers in Biology and Medicine

    • Unveiling the cancer risk nexus of the steatotic liver

      2024, Trends in Endocrinology and Metabolism

    • Cellular and Molecular Techniques

      2023, MacSween's Pathology of the Liver, Eighth Edition

    • Role of genetic testing in hepatic, pancreatic, and biliary cancers

      2022, Surgical Oncology

    • Mechanisms of drug resistance in HCC

      2024, Hepatology

    • The efficacy-associated biomarkers for immune checkpoint inhibitors in gastrointestinal cancer: a literature review

      2024, Journal of Gastrointestinal Oncology
    View all citing articles on Scopus

    Conflicts of interest This author discloses the following: Lewis R. Roberts received grant funding from Ariad Pharmaceuticals, Bayer, BTG International, Exact Sciences, Gilead Sciences, RedHill Biopharma, TARGET PharmaSolutions, and Wako Diagnostics, and was on the Advisory Board at Bayer, Exact Sciences, Gilead Sciences, RedHill Biopharma, TAVEC, and Wako Diagnostics. The remaining authors disclose no conflicts.

    Funding Renumathy Dhanasekaran: National Institutes of Health (NIH) grant CA222676 from the National Cancer Institute (NCI), American College of Gastroenterology Junior Faculty Career Development Grant. Lewis R. Roberts: grant numbers CA165076 and CA186566 from the NCI, the Mayo Clinic Hepatobiliary Specialized Program of Research Excellence (NCI CA210964), the Mayo Clinic Center for Cell Signaling in Gastroenterology (National Institute of Diabetes and Digestive and Kidney Diseases P30DK084567), the Mayo Clinic Cancer Center (CA15083), and the Mayo Clinic Center for Translational Science Activities (NIH/National Center for Research Resources Clinical and Translational Science Awards grant number UL1 TR000135). Jean-Charles Nault and Jessica Zucman-Rossi: Supported by Institut National du Cancer (INCa) with the International Cancer Genome Consortium (ICGC LICA-FR project) and NoFLIC projects (PAIR HCC, INCa, and ARC), Institut National de la Santé et de la Recherche Médicale with the Cancer et Environnement (plan Cancer), Mutational Landscape in Hepatocellular Carcinoma projects (INCa) and the Hepatocellular Carcinoma Multi-Technological project (BPI). The group is supported by the Ligue Nationale Contre le Cancer (Equipe Labellisée), Labex OncoImmunology (investissement d’avenir), grant IREB, Coup d’Elan de la Fondation Bettencourt-Shueller, the Site de Recherche Intégrée sur le Cancer Cancer Research and Personalized Medicine and Fondation Mérieux.

    View full text
    © 2019 by the AGA Institute