Analysis of mutational landscape and genetic heterogeneity in liver cancer with whole genome sequencing. A. Fujimoto1, M. Furuta1, Y. Shiraishi2, H. H. Nguyen1, D. Shigemizu1, K. Gotoh3, Y. Kawakami4, T. Nakamura5, M. Ueno6, S. Ariizumi7, T. Shibata8, H. Ojima8, K. Shimada8, S. Hayami6, Y. Shigekawa6, H. Aikata4, K. Arihiro4, H. Ohdan4, S. Marubashi3, T. Yamada3, O. Ishikawa3, M. Kubo1, S. Hirano5, M. Yamamoto7, H. Yamaue6, K. Chayama1,4, S. Miyano2, T. Tsunoda1, H. Nakagawa1 1) RIKEN Center for Integrative Medical Sciences; 2) Human Genome Center, The Institute of Medical Science, The University of Tokyo; 3) Osaka Medical Center for Cancer and Cardiovascular Diseases; 4) Hiroshima University School of Medicine; 5) Hokkaido University Graduate School of Medicine; 6) Wakayama Medical University; 7) Tokyo Womens Medical University; 8) National Cancer Center.
Primary liver cancers can be generally classified into hepatocellular carcinomas (HCCs) and liver cancer with biliary phenotype (LCB). To elucidate comprehensive genetic landscape of liver cancer, we performed whole genome sequence of sixty HCCs and fifteen LCBs, and identified point mutations, short indels, copy number alternation and rearrangements. While the genome-wide substitution pattern of LCBs that developed in livers affected by hepatitis overlapped with those of HCCs, the substitution patterns of LCBs without a hepatitis background diverged and were closer to liver fluke-related cholangiocarcinoma and pancreatic cancer, suggesting the influence of hepatitis and/or cellular origin on the substitution pattern. Whole genome sequencing and the subsequent validation study identified recurrent mutations in chromatin regulators, KRAS (specifically mutated in hepatitis-free LCBs), and other new pathways, in addition to known cancer-related genes such as TP53 and CTNNB1. Examination of intra-tumor heterogeneity by deep sequencing suggests that the distribution of clonal proportion reflect tumor type, and that mutations in various genes can contribute to tumor initiation in liver.
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