Genetics and epigenetics of liver cancer

Abstract

Hepatocellular carcinoma (HCC) represents a major form of primary liver cancer in adults. Chronic infections with hepatitis B (HBV) and C (HCV) viruses and alcohol abuse are the major factors leading to HCC. This deadly cancer affects more than 500,000 people worldwide and it is quite resistant to conventional chemo- and radiotherapy. Genetic and epigenetic studies on HCC may help to understand better its mechanisms and provide new tools for early diagnosis and therapy. Recent literature on whole genome analysis of HCC indicated a high number of mutated genes in addition to well-known genes such as TP53, CTNNB1, AXIN1 and CDKN2A, but their frequencies are much lower. Apart from CTNNB1 mutations, most of the other mutations appear to result in loss-of-function. Thus, HCC-associated mutations cannot be easily targeted for therapy. Epigenetic aberrations that appear to occur quite frequently may serve as new targets. Global DNA hypomethylation, promoter methylation, aberrant expression of non-coding RNAs and dysregulated expression of other epigenetic regulatory genes such as EZH2 are the best-known epigenetic abnormalities. Future research in this direction may help to identify novel biomarkers and therapeutic targets for HCC.

Chronic alcohol drinking: Liver and pancreatic cancer?

“…In addition, a large number of genes and pathways that are subject to epigenetic dysregulation play an important role during the development and progression of HCC [29]. Global DNA hypomethylation, histone modifications, promoter methylation, and aberrant expression of non-coding RNAs are the best-known epigenetic abnormalities [30]. Alcohol metabolism alters the ratio of NAD + to NADH and promotes the formation of ROS, which impacts on epigenetic regulatory mechanisms.…”

DNA markers in molecular diagnostics for hepatocellular carcinoma

“…A great deal of work has been devoted to identifying such DNA modi fications as potential biomarkers for the early detection of cancer. In general, the number of candidate cancer biomarkers has exploded since the introduction of genome wide sequencing of diseased tissue DNA, using NGS [11–15,18,19,31–33] and genome wide methylation study using methylation arrays [34–37]. However, such identification will only be useful for cancer screening and the early detection of cancer, if it can be done in the periphery in a non-invasive or minimally invasive manner.…”

“…Like other cancers, HCC is a disease of the genome, caused by genetic and epigenetic DNA modifications [9–11]. Identification of the DNA modifications (mutation or methylation) underlying the development of HCC should permit unambiguous diagnosis of HCC cases.…”

“…The introduction of noct generation sequencing (NGS) has lead to the identification of many of such modifications, associating with HCC tissues. A significant amount of work has fucused on distinguishing the drivers from the passengers of these DNA modifications, in combination with studying the pathways involved in carcinogenesis to determine how these DNA modifications can be used as potential markers for HCC detection [11–19]. However, these candidate DNA markers will not be useful for either diagnosis or surveillance unless they can be detected in the peripherals, without liver biopsy.…”

Long noncoding RNA, the methylation of genomic elements and their emerging crosstalk in hepatocellular carcinoma

“…Genomic instability and accumulated mutation are some of the signatures of cancer and are considered to be helpful in the field of cancer research. Besides, epigenetic alterations, including abnormal DNA methylation, chromatin modification and noncoding RNA, are partly heritable like genetic mutation and implicated in multiple cancers [6,7]. A report by other groups resumed the detailed features of lncRNA, especially the aberrant expression, biological functions, molecular mechanisms and potential clinical application of lncRNA in carcinogenesis and progression of HCC, supplying a full landscape of lncRNA in HCC.…”