Patterns Of Somatic Mutations In Hepatitis B Virus-Associated Hepatocellular Carcinomas

Background and Aim:Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide with an annual incidence of 523,432 cases,56% of which are in China. The estimated mortality is 266,830 cases deaths a year in China. The risk factors for HCC include infection with hepatitis-B virus (HBV) or hepatitis-C virus (HCV), alcoholic liver disease, and most probably nonalcoholic fatty liver disease. At present, many studies have been performed to define the molecular mechanisms underlying hepatocarcinogenesis. Several genes have been shown to be involved in genetic and epigenetic events in HCC, including tumor suppressor genes (ie, TP53). In addition, HCC also showed large-scale genomic alterations, including single nucleotide variants (SNVs) and chromosomal structural aberrations. Recent studies have reported genetic basis of HCC using the technology of next-generation sequencing. However, the patterns of somatic mutations in the liver cancer and its matched cirrhotic tissues were not fully characterized.Methods:1. We performed whole-exome sequencing on liver cancer tissues, its matched cirrhotic liver tissues and peripheral blood leukocyte (PBL) in 13 patients of hepatitis B virus-associated HCC.2. We constructed a bioinformatics platform, to identify tumor somatic mutations.3. We characterized mutational landscape of 13 HCCs.Results:Whole-exome sequencing resulted in approximate 106 million raw reads with an average coverage of 110× in each sample. The prevalence of somatic mutations differed significantly among HCCs. Among 6,972 non-silent mutations (i.e., missense, nonsense mutations, splice sites and translation start sites) identified in 13 HCC patients, we found that T:A>A:T transversion showed the highest percentage of non-silent mutations, followed by C:G>T:A transversion and C:G>A:T transversion. By comparison of somatic mutations identified in liver cancer tissues and cirrhotic tissues, we found that somatic mutations were not accumulated in genes in HBV-associated cirrhotic liver tissues. Notably, two genes (TP53 and KRTAP4-3) were shown to be significantly mutated by MutSigCV analysis, suggesting that there were evidence for’driver’mutations of these genes contributing to the development of liver cancer.Conclusion:Next-generation sequencing technology has been broadly applied in the field of life sciences. Its characteristics include large amount of data, lower price and shorter sequencing period. Our study characterized the patterns of HCCs somatic mutation and discovered potential diver mutations underlying HBV-associated HCC.