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Multiregional whole‐genome sequencing of hepatocellular carcinoma with nodule‐in‐nodule appearance reveals stepwise cancer evolution
Author(s) -
Takeda Haruhiko,
Takai Atsushi,
Kumagai Ken,
Iguchi Eriko,
Arasawa Soichi,
Eso Yuji,
Shimizu Takahiro,
Ueda Yoshihide,
Taura Kojiro,
Uemoto Shinji,
Kita Ryuichi,
Haga Hironori,
Marusawa Hiroyuki,
Fujimoto Akihiro,
Seno Hiroshi
Publication year - 2020
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.5533
Subject(s) - hccs , hepatocellular carcinoma , biology , point mutation , cancer research , liver cancer , nodule (geology) , mutation , gene , genetics , paleontology
Recent genetic analyses revealed genetic heterogeneity in hepatocellular carcinoma (HCC), although it remains unclear how genetic alterations contribute to the multistage progression of HCC, especially the early step from hypovascular liver nodules to hypervascular HCC. We conducted multiregional whole‐genome sequencing on HCCs with a nodule‐in‐nodule appearance, consisting of inner hypervascular HCC surrounded by hypovascular HCC arising from a common origin, and identified point mutations, structural variations, and copy‐number variations in each specimen. According to the genetic landscape of the inner and outer regions, together with the pathological and radiological findings, we examined the stepwise evolution of cancer cells from slow‐growing HCC to rapid‐growing HCC. We first demonstrated that most tumor cells consisting of hypovascular well‐differentiated HCCs already harbored thousands of point mutations and even several structural variations, including chromosomal translocations and chromothripsis, as the trunk events. Telomerase reverse transcriptase ( TERT )‐associated aberrations, including promoter mutations, chromosomal translocation, and hepatitis B virus DNA integration, as well as abnormal methylation status, were commonly detected as the trunk aberrations, while various liver cancer‐related genes, which differed in each case, had additionally accumulated in the inner dedifferentiated nodules. Further, differences in the trunk and branch mutational signatures suggested a multistep contribution to the mutagenesis in each case. In conclusion, genomic alterations associated with the TERT gene could be the key driver events to form the hypovascular HCC, and additional case‐specific driver mutations accumulate during the progression phase, forming intra‐ and inter‐tumoral heterogeneity, confirming the importance of genetic testing before targeting therapy. These data shed light on the process of multistep hepatocarcinogenesis and will be helpful toward investigating new therapeutic strategies for HCC. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.