Abstract
BackgroundRecently, a number of studies have performed genome or exome sequencing of hepatocellular carcinoma (HCC) and identified hundreds or even thousands of mutations in protein-coding genes. However, these studies have only focused on a limited number of candidate genes, and many important mutation resources remain to be explored.Principal FindingsIn this study, we integrated mutation data obtained from various sources and performed pathway and network analysis. We identified 113 pathways that were significantly mutated in HCC samples and found that the mutated genes included in these pathways contained high percentages of known cancer genes, and damaging genes and also demonstrated high conservation scores, indicating their important roles in liver tumorigenesis. Five classes of pathways that were mutated most frequently included (a) proliferation and apoptosis related pathways, (b) tumor microenvironment related pathways, (c) neural signaling related pathways, (d) metabolic related pathways, and (e) circadian related pathways. Network analysis further revealed that the mutated genes with the highest betweenness coefficients, such as the well-known cancer genes TP53, CTNNB1 and recently identified novel mutated genes GNAL and the ADCY family, may play key roles in these significantly mutated pathways. Finally, we highlight several key genes (e.g., RPS6KA3 and PCLO) and pathways (e.g., axon guidance) in which the mutations were associated with clinical features.ConclusionsOur workflow illustrates the increased statistical power of integrating multiple studies of the same subject, which can provide biological insights that would otherwise be masked under individual sample sets. This type of bioinformatics approach is consistent with the necessity of making the best use of the ever increasing data provided in valuable databases, such as TCGA, to enhance the speed of deciphering human cancers.
Highlights
Hepatocellular carcinoma (HCC) is the third most frequent cause of cancer-related mortality worldwide and is usually associated with specific risk factors, including hepatitis B or C infection, high alcohol intake, hemochromatosis or nonalcoholic fatty liver disease caused by obesity and insulin resistance [1]
To complete the mutation landscape of hepatocellular carcinoma (HCC), a number of studies have recently performed genome or exome sequencing of HCC and identified hundreds or even thousands of mutations in protein-coding genes [1,4,5,6,7]. These studies have confirmed some important alterations and more importantly, revealed novel alterations that have refined our knowledge of the mutational landscape and the related signaling pathways involved in liver carcinogenesis
Data obtained from the International Cancer Genome Consortium (ICGC) and Kan et al with larger samples detected 4376 and 3702 mutated genes, respectively, whereas data obtained from Li et al and Huang et al contained smaller samples that detected 398 and 347 mutated genes, respectively
Summary
Hepatocellular carcinoma (HCC) is the third most frequent cause of cancer-related mortality worldwide and is usually associated with specific risk factors, including hepatitis B or C infection, high alcohol intake, hemochromatosis or nonalcoholic fatty liver disease caused by obesity and insulin resistance [1]. To complete the mutation landscape of HCC, a number of studies have recently performed genome or exome sequencing of HCC and identified hundreds or even thousands of mutations in protein-coding genes [1,4,5,6,7] These studies have confirmed some important alterations (e.g., mutations in CTNNB1, AXIN1, TP53, CDKN2A, etc.) and more importantly, revealed novel alterations (e.g., mutations in ARID2, ARID1A, NRF2, etc.) that have refined our knowledge of the mutational landscape and the related signaling pathways involved in liver carcinogenesis. These studies have only focused on a limited number of candidate genes, and many important mutation resources remain to be explored
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