ReviewGenetic profiling of hepatocellular carcinoma using next-generation sequencing
Introduction
Hepatocellular carcinoma (HCC) is the second cause of cancer-related mortality worldwide [1]. Its mortality is rising and considering the dismal results of recent clinical trials testing systemic agents [2], it seems more difficult to treat than initially anticipated. Each HCC is composed of a unique combination of somatic alterations including genetic, epigenetic, transcriptomic and metabolic events that form its unique molecular fingerprint [3], [4]. Regarding genetic changes, the progressive accumulation of mutations in cancer cells is the result of spontaneous events in the context of enhanced cell division, exposure to viruses (e.g., hepatitis B), carcinogens (e.g., aflatoxin B1) and defects in the DNA repair processes [5]. Moreover, the strong association between cirrhosis and HCC could be partially explained by an accelerated acquisition of genetic alterations in senescent cirrhotic hepatocytes exposed to chronic inflammation and oxidative stress [6]. Genome wide sequencing using next-generation technologies has exponentially improved our ability to explore the cancer genome [7]. Identification of the key driver genes and mechanisms underlying mutation occurrence could help understand HCC pathogenesis and develop new therapeutic strategies [2]. Herein, we will review the main advances in our knowledge of the HCC genome obtained by next-generation sequencing (NGS) and its potential future impact in clinical practice.
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Methodological insights of next-generation sequencing
It took almost 40 years between the identification of the structure of DNA [8] by Watson, Crick and Wilkins (Nobel Prize 1962) and the first draft of the complete sequence of the human genome after 10 years of work for almost 4 billion US dollars [9]. NGS technologies developed in the beginning of the 21st century considerably accelerated our ability to explore the DNA structure at a significant lower cost (less than $5000 for a whole human genome performed in less than 24 h) [10]. NGS generates
Mutational landscape in hepatocellular carcinoma
The accumulation of alterations in cancer driver genes and associated pathways are major triggers for hepatocarcinogenesis and tumor progression. Specific discrepancies in HCC mutation rates of major cancer drivers are thought to be dependent on the clinical profile of each patient such as etiology of the liver disease, stage of cancer progression, selective pressure under treatment, and presence or not of an underlying chronic liver disease. Therefore, deciphering the mutational landscape of
Mutational signatures in hepatocellular carcinoma
In addition to identifying mutations in specific genes and their potential contribution to the malignant phenotype, a more global view on mutational patterns has been recently developed at the Wellcome Trust Sanger Institute. The so-called ‘nucleotide or mutational signatures’ link distinct intrinsic processes such as defective DNA repair or exposure to external toxic agents (e.g., UV light, tobacco) with specific patterns of mutations at the nucleotide level. Taking into account a nucleotide
Genetic basis of telomerase reactivation in hepatocellular carcinoma
Telomeres are short non-coding DNA repeats (TTAGGG) localized at the extremity of the chromosome and coated by sheltering proteins [31]. They protect coding regions from DNA losses induced by the shortening of the end of the chromosome due to the end replication problem observed during cell division [32], [33]. However, at each round of cell replication, telomeres shortened and, when they reach a critical point, cell senescence is triggered through induction of the P53/P21 and P16/RB
Consequences of viral infection for the genome of hepatocellular carcinoma
The most common mechanism leading to HCC in patients with chronic viral infection remains the occurrence of chronic liver disease and cirrhosis due to persistent inflammation and oxidative stress [3]. A direct oncogenic role of HCV proteins is still controversial, and since HCV is an RNA virus no integrations in the tumor genome have been described [55]. This mechanism explains most HCV-related HCC since these patients almost always develop HCC on cirrhosis. In contrast, a direct oncogenic
Molecular heterogeneity in hepatocellular carcinoma
The issue of cancer molecular heterogeneity has sparked notorious scientific debate in the last years. The concept assumes that somatic molecular alterations in cancer are not uniformly distributed throughout the whole tumor mass. One of the key issues is to determine if this diversity significantly impacts predictions based on single biopsies, and ultimately, clinical decision-making in the precision medicine era. Molecular heterogeneity expands the model of clonal cancer evolution, which was
Clinical implementation of sequencing data
One of the most notorious successes of anticancer therapy came from the selective blockage of cancer drivers [98]. Some of them are the result of aberrant activation of tyrosine kinases due to somatic mutation. Well-known examples include erlotinib in EGFR-mutated lung cancer, vemurafenib in BRAF-mutated melanoma or crizotinib in lung cancer with anaplastic lymphoma kinase (ALK) rearrangements. Unfortunately, biomarker-driven clinical trials haven’t dominated drug development in HCC. Probably
Conclusions and future perspectives
The tremendous impact that NGS had in biomedical research is indisputable. Like in previous occasions, technological breakthroughs had preceded major scientific discoveries. In the case of HCC, one of the deadliest malignancies known to humans, NGS has provided a comprehensive landscape of recurrence molecular alterations including somatic mutations, chromosomal alterations and viral integrations. Further analytical refinements of NGS data will soon allow to better understand tumor
Conflict of interest
The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
Acknowledgments
AV is the recipient of the American Association for the Study of Liver Diseases Foundation Alan Hofmann Clinical and Translational Research Award.
References (109)
Pathogenesis of hepatocellular carcinoma according to aetiology
Best Pract Res Clin Gastroenterol
(2014)- et al.
Identification of a therapeutic strategy targeting amplified FGF19 in liver cancer by Oncogenomic screening
Cancer Cell
(2011) - et al.
Mutational signatures: the patterns of somatic mutations hidden in cancer genomes
Curr Opin Genet Dev
(2014) - et al.
Deciphering signatures of mutational processes operative in human cancer
Cell Rep
(2013) - et al.
The role of telomeres in stem cells and cancer
Cell
(2013) - et al.
TERT promoter mutations in primary liver tumors
Clin Res Hepatol Gastroenterol
(2016) - et al.
Hepatocellular benign tumors-from molecular classification to personalized clinical care
Gastroenterology
(2013) - et al.
Genomic profiling of hepatocellular adenomas reveals recurrent FRK-activating mutations and the mechanisms of malignant transformation
Cancer Cell
(2014) - et al.
Pathogenesis and prevention of hepatitis C virus-induced hepatocellular carcinoma
J Hepatol
(2014) - et al.
Mechanisms of HBV-related hepatocarcinogenesis
J Hepatol
(2010)
Interaction of hepatitis B viral oncoprotein with cellular target HBXIP dysregulates centrosome dynamics and mitotic spindle formation
J Biol Chem
Pathogenesis of hepatitis B virus-related hepatocellular carcinoma: old and new paradigms
Gastroenterology
Antibodies to adeno-associated satellite virus and herpes simplex in sera from cancer patients and normal adults
Am J Obstet Gynecol
Clonality analysis for multicentric origin and intrahepatic metastasis in recurrent and primary hepatocellular carcinoma
J Gastrointest Surg
Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy
J Hepatol
Risk factors for early and late recurrence in hepatitis B-related hepatocellular carcinoma
J Hepatol
Chromosomal changes and clonality relationship between primary and recurrent hepatocellular carcinoma
Gastroenterology
Diagnosis of intrahepatic metastasis and multicentric carcinogenesis by microsatellite loss of heterozygosity in patients with multiple and recurrent hepatocellular carcinomas
J Hepatol
Variable intra-tumor genomic heterogeneity of multiple lesions in patients with hepatocellular carcinoma
Gastroenterology
Biological and therapeutic impact of intratumor heterogeneity in cancer evolution
Cancer Cell
Targeted therapies for hepatocellular carcinoma
Gastroenterology
Tivantinib for second-line treatment of advanced hepatocellular carcinoma: a randomised, placebo-controlled phase 2 study
Lancet Oncol
Global cancer statistics, 2012
CA Cancer J Clin
Advances in targeted therapies for hepatocellular carcinoma in the genomic era
Nat Rev Clin Oncol
Functional and genetic deconstruction of the cellular origin in liver cancer
Nat Rev Cancer
The genetic landscape and biomarkers of hepatocellular carcinoma
Gastroenterology
The cancer genome
Nature
Advances in understanding cancer genomes through second-generation sequencing
Nat Rev Genet
Genetical implications of the structure of deoxyribonucleic acid
Nature
Initial sequencing and analysis of the human genome
Nature
Sequencing technologies - the next generation
Nat Rev Genet
Cancer genome landscapes
Science
Evolution of the cancer genome
Nat Rev Genet
Personalized oncology through integrative high-throughput sequencing: a pilot study
Sci Transl Med
Signatures of mutational processes in human cancer
Nature
Trans-ancestry mutational landscape of hepatocellular carcinoma genomes
Nat Genet
Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets
Nat Genet
Toward understanding and exploiting tumor heterogeneity
Nat Med
Exploring the genomes of cancer cells: progress and promise
Science
Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators
Nat Genet
Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma
Nat Genet
Exome sequencing of hepatitis B virus-associated hepatocellular carcinoma
Nat Genet
Identification of driver genes in hepatocellular carcinoma by exome sequencing
Hepatology
Whole-genome sequencing identifies recurrent mutations in hepatocellular carcinoma
Genome Res
Genomic portrait of resectable hepatocellular carcinomas: implications of RB1 and FGF19 aberrations for patient stratification
Hepatology
Genetic landscape and biomarkers of hepatocellular carcinoma
Gastroenterology
Human and mouse VEGFA-amplified hepatocellular carcinomas are highly sensitive to sorafenib treatment
Cancer Discov
Genome-wide mutational signatures of aristolochic acid and its application as a screening tool
Sci Transl Med
Telomere diseases
N Engl J Med
The telomere syndromes
Nat Rev Genet
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