ReviewMolecular prognostication of liver cancer: End of the beginning
Introduction
New technological developments have frequently preceded major advances in biomedical research and medicine [1]. For example, the development of fluorescent DNA sequencing techniques made it possible to establish the large-scale high-throughput technology needed for human genome sequencing. Polymerase chain reaction (PCR), fluorescent DNA sequencing, and other techniques have enabled the discovery of about 1700 mendelian disease genes [2]. The advent of the DNA microarray based technologies has now made it possible to measure simultaneously the expression of tens of thousands of genes in different tissues under a variety of conditions. This high-throughput technology has afforded biomedical scientists a unique opportunity to integrate the descriptive characteristics (i.e. ‘phenotype’) of a biological system under study with the genomic readout (i.e. gene expression). The opportunity to contemplate the integrated view of biological systems has provoked a shift in biological sciences away from the classical reductionism to systems biology [1], [3], [4]. The systems approach to a disease is based on the hypothesis that disease processes perturb a regulatory network of genes and proteins in a way that differs from the respective normal counterpart. Consequently, by using multi-parametric measurements it may be possible to transform current diagnostic and therapeutic approaches and enable a predictive and preventive personalized medicine [4].
The application of microarray technologies to characterize tumors at the gene expression level has significantly impacted clinical oncology [5], [6]. Global gene expression analysis of various human tumors has resulted in the identification of gene expression patterns or signatures related to tumor classification, disease outcome and response to therapy. The microarray technology has also been used to investigate the mechanism of action of specific cancer therapeutics. In this review, we will briefly discuss the general impact of the global gene expression analysis on cancer research and devote the rest to the microarray based gene expression analysis of human hepatocellular carcinoma (HCC).
Section snippets
Tumor classification and prognostic prediction
It is well established that cancer even in the same tissue is a very heterogeneous disease that differs widely in clinical outcome and in response to therapy. It is now clear that this heterogeneity is due to different molecular defects that can induce similar tumor phenotypes. Although, histopathological and biochemical markers constitute important tools for identifying groups of tumors that differ with respect to prognosis and responses to treatments, the genes and molecular pathways
Predicting HCC prognosis
Hepatocellular carcinoma (HCC) is one of the most common cancers in the world, accounting for an estimated 600,000 deaths annually [17]. While HCC is common in southeast Asia and sub-Sahara Africa, the incidence rates of HCC have continued to increase in the United States and western Europe over the past 25 years and the incidence and mortality rates of HCC are expected to double over the next 10–20 years [18], [19], [20]. Although much is known about both the cellular changes that lead to HCC
Molecular profiling of HCC
Numerous studies dealing with gene expression profiling of HCC have appeared during the last 5 years (see Table 1). In addition, several review articles addressing the application of the DNA microarray platform in studies on HCC have recently been published [35], [36], [37], [38], [39]. The molecular profiling of HCC presents challenges that are not commonly seen in other human tumors. This is primarily due to the complex pathogenesis of this cancer [23]. HCC arises most commonly in cirrhotic
Survival
It has long been recognized that survival prediction of HCC patients is more challenging than with most other cancers. This is, in the cases of HBV and HCV, the consequence of the underlying viral driven non-neoplastic disease, i.e. chronic hepatitis and cirrhosis that can and does inflict functional impairment on the liver that may affect the outcome of the HCC patients. However, in a recent study on survival of HCC patients, it was demonstrated that the HCC was the prime cause of death in
Conclusion and perspective
Profiling liver cancer and indeed cancer in general with gene expression arrays has become common. The results from early studies, particularly those unraveling novel cancer classifications and identifying novel markers for prediction of clinical outcome, kindled the hope that this technology would provide understanding of the molecular differences between clinical cases and allow individualization of care. There can be no doubt that the DNA microarray technology has provided an extraordinary
References (55)
- et al.
The biology of human lymphoid malignancies revealed by gene expression profiling
Adv Immunol
(2005) - et al.
Hepatitis C infection and the increasing incidence of hepatocellular carcinoma: a population-based study
Gastroenterology
(2004) - et al.
Focus on hepatocellular carcinoma
Cancer Cell
(2004) - et al.
Hepatocellular carcinoma
Lancet
(2003) - et al.
HCC surveillance: who is the target population?
Hepatology
(2003) - et al.
A new prognostic classification for predicting survival in patients with hepatocellular carcinoma. Groupe d'Etude et de Traitement du Carcinome Hepatocellulaire
J Hepatol
(1999) - et al.
Genome-scale profiling of gene expression in hepatocellular carcinoma: classification, survival prediction, and identification of therapeutic targets
Gastroenterology
(2004) - et al.
Oligonucleotide microarray for prediction of early intrahepatic recurrence of hepatocellular carcinoma after curative resection
Lancet
(2003) - et al.
Molecular-based prediction of early recurrence in hepatocellular carcinoma
J Hepatol
(2004) - et al.
Increased survival of cirrhotic patients with a hepatocellular carcinoma detected during surveillance
Gastroenterology
(2004)
When protein destruction runs amok, malignancy is on the loose
Cancer Cell
Prediction of cancer outcome with microarrays: a multiple random validation strategy
Lancet
Genomic medicine and the future of health care
Science
Realizing the promise of genomics in biomedical research
J Am Med Assoc
Systems biology and new technologies enable predictive and preventative medicine
Science
Clinical application of cDNA microarrays in oncology
Oncologist
Gene expression-driven diagnostics and pharmacogenomics in cancer
Curr Opin Mol Ther
Molecular classification of cutaneous malignant melanoma by gene expression profiling
Nature
Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling
Nature
Gene-expression profiles predict survival of patients with lung adenocarcinoma
Nat Med
A gene-expression signature as a predictor of survival in breast cancer
N Engl J Med
Prognostically useful gene-expression profiles in acute myeloid leukemia
N Engl J Med
Classification and prediction of survival in hepatocellular carcinoma by gene expression profiling
Hepatology
An expression profile for diagnosis of lymph node metastases from primary head and neck squamous cell carcinomas
Nat Genet
Pharmacogenomic analysis of cytogenetic response in chronic myeloid leukemia patients treated with imatinib
Clin Cancer Res
Molecular classification and molecular forecasting of breast cancer: ready for clinical application?
J Clin Oncol
Cited by (68)
G6PD inhibits ferroptosis in hepatocellular carcinoma by targeting cytochrome P450 oxidoreductase
2021, Cellular SignallingNongenotoxic Carcinogenesis
2018, Comprehensive Toxicology: Third EditionNovel substituted aminothiazoles as potent and selective anti-hepatocellular carcinoma agents
2016, Bioorganic and Medicinal Chemistry LettersTargeting autophagy for the treatment of liver diseases
2012, Pharmacological ResearchCitation Excerpt :However, the incidence of HCC has increased in the US and western Europe over the past 25 years. Viral infection, such as HBV (mainly in Asia and Africa) and HCV (mainly in western countries and Japan), as well as alcohol abuse are responsible for the majority of HCC, but the exact molecular pathogenesis is not yet well understood [110,111]. HCC is a highly malignant and fatal neoplasia.
Deregulation of signalling pathways in prognostic subtypes of hepatocellular carcinoma: Novel insights from interspecies comparison
2012, Biochimica et Biophysica Acta - Reviews on CancerPre-operative liver biopsy in cirrhotic patients with early hepatocellular carcinoma represents a safe and accurate diagnostic tool for tumour grading assessment
2011, Journal of HepatologyCitation Excerpt :However, the Milan criteria are based only on strict morphologic evaluations, without any consideration of the tumour histology. On the contrary, the histological characteristics of the tumour could have the same clinical significance as the radiological criteria in determining patient outcome after OLT [6,7] Moreover, histological evaluation could play an important role in confirming the diagnosis of HCC and in the assessment of the biological behaviour of the tumour. Furthermore, imaging can either understage or overstage HCC; in fact, in a review of the United Network for Organ Sharing (UNOS) database, 31% of patients who underwent OLT for HCC based on imaging results were found not to have HCC [8]; on the contrary, others [9] have observed that pre-OLT imaging understaged the disease in 15–25% of cases.