Comparison of genomic alterations in tumor and non-tumorous tissues revealed stepwise mechanism of hepatocarcinogenesis

Hepatocellular carcinoma is a multi-factor disease induced by hepatitis virus infection, metabolic syndrome, alcohol intakes and chemical carcinogens. These conditions cause the chronic hepatitis, fibrosis and cirrhosis, and eventually the development of carcinoma. Cellular and histological changes are supposed to be a first steps for hepatocellular carcinoma and the fibrotic liver background is considered as pre-carcinogenic lesion. However, the genetic alterations in non-cancerous cells and the origin of tumor cell are still under investigating. Here, we performed exome and targeted sequencing analysis to understand the stepwise mechanism of hepatic carcinogenesis. Mutational signature analysis (96 triplet types) showed the nucleotide change patter in tumor and adjacent non-tumor tissue is similar in each patient. Somatic mutations in tumor were relatively high allele fraction and recurrently mutated genes have a role in telomerase, TP53, WNT/β-catenin, chromatin remodeling and epigenetic modifiers pathways. However, somatic mutations in non-tumor and normal tissues were low allele fraction. Although almost somatic mutations between tumor and non-tumor sites were distinct, mutations in TERT promoter were recurrently mutated even in non-tumorous sites. Baysiane model method inferred tumor cell clone harboring driver mutation were different origins from non-tumor cell clone. These results suggest the normal liver cells under the chronic stresses have high chances of occurrence to genetic alterations, and eventually driver mutation.