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Multiregional whole-genome sequencing of hepatocellular carcinoma with nodule-in-nodule appearance reveals stepwise cancer evolution
- Source :
- The Journal of pathologyReferences. 252(4)
- Publication Year :
- 2020
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
Male
Carcinoma, Hepatocellular
DNA Copy Number Variations
Carcinogenesis
Biology
Pathology and Forensic Medicine
03 medical and health sciences
0302 clinical medicine
medicine
Biomarkers, Tumor
Early Hepatocellular Carcinoma
Humans
Telomerase reverse transcriptase
Promoter Regions, Genetic
Genetic testing
Aged
Cell Proliferation
Chromothripsis
medicine.diagnostic_test
Whole Genome Sequencing
Genetic heterogeneity
Point mutation
Liver Neoplasms
HCCS
Middle Aged
medicine.disease
digestive system diseases
030104 developmental biology
030220 oncology & carcinogenesis
Hepatocellular carcinoma
Mutation
Cancer research
Disease Progression
Female
Subjects
Details
- ISSN :
- 10969896
- Volume :
- 252
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- The Journal of pathologyReferences
- Accession number :
- edsair.doi.dedup.....096e857c60bef2164b84e475987e3298