Correlation between CTNNB1 mutation status and tumour phenotype in hepatitis B virus-related hepatocellular carcinoma
Yoon Jung Hwang
Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Korea
Search for more papers by this authorYangkyu Lee
Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
Department of Pathology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
Search for more papers by this authorSu Jong Yu
Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine; Biomedical Research Institute, Center for Medical Innovation, Seoul National University Hospital, Seoul, Korea
Search for more papers by this authorSuk Kyun Hong
Department of Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
Search for more papers by this authorNam-Joon Yi
Department of Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
Search for more papers by this authorYoungRok Choi
Department of Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
Search for more papers by this authorHyejung Lee
Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
Search for more papers by this authorWonju Chung
Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
Department of Pathology, Seoul National University Hospital, Seoul, Korea
Search for more papers by this authorCorresponding Author
Haeryoung Kim
Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
Department of Pathology, Seoul National University Hospital, Seoul, Korea
Address for correspondence: Haeryoung Kim, Department of Pathology, Seoul National University College of Medicine, 103 Daehak-no, Jongno-gu, Seoul 03080, Korea.
e-mail: [email protected]
Search for more papers by this authorYoon Jung Hwang
Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Korea
Search for more papers by this authorYangkyu Lee
Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
Department of Pathology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
Search for more papers by this authorSu Jong Yu
Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine; Biomedical Research Institute, Center for Medical Innovation, Seoul National University Hospital, Seoul, Korea
Search for more papers by this authorSuk Kyun Hong
Department of Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
Search for more papers by this authorNam-Joon Yi
Department of Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
Search for more papers by this authorYoungRok Choi
Department of Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
Search for more papers by this authorHyejung Lee
Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
Search for more papers by this authorWonju Chung
Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
Department of Pathology, Seoul National University Hospital, Seoul, Korea
Search for more papers by this authorCorresponding Author
Haeryoung Kim
Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
Department of Pathology, Seoul National University Hospital, Seoul, Korea
Address for correspondence: Haeryoung Kim, Department of Pathology, Seoul National University College of Medicine, 103 Daehak-no, Jongno-gu, Seoul 03080, Korea.
e-mail: [email protected]
Search for more papers by this authorAbstract
Aims
The frequency of CTNNB1 mutation, one of the most frequent genetic events in hepatocellular carcinoma (HCC), is lower in Asian countries and in hepatitis B virus (HBV)-related HCCs. In this study, we evaluated the prevalence and types of CTNNB1-mutation in HBV-related HCC and correlated the molecular status with the histomorphological and immunohistochemical features.
Methods and results
A total of 108 consecutive cases of treatment-naïve, surgically resected HBV-related HCCs were selected. Targeted sequencing for CTNNB1 exons 3, 7 and 8 was performed, and the results were correlated with the expression pattern of glutamine synthetase (GS), nuclear β-catenin expression status and the histomorphological characteristics of the tumour. CTNNB1 mutations were identified in 13% of HBV-related HCCs; of these cases, mutations were found in D32-S37 (7%), T41 (4%) and S45 (2%) of exon 3. None of the HCCs demonstrated alterations in exons 7 and 8. CTNNB1 mutation was strongly associated with diffuse strong GS expression (P < 0.001), nuclear β-catenin expression (P < 0.001) and the classic CTNNB1 morphology (P = 0.038). Diffuse strong GS expression was observed in 78.6% of the CTNNB1-mutated HCCs, and nuclear β-catenin expression was identified in 64.3% of these cases. The classic CTNNB1 morphology was observed in 57% of all CTNNB1-mutated HCCs. Furthermore, programmed death-ligand 1 (PD-L1) was less frequently expressed in HCCs with classic CTNNB1 morphology.
Conclusions
CTNNB1 mutation was observed in 13% of HBV-related HCCs in this Korean cohort, and was associated with diffuse strong GS expression, nuclear β-catenin expression and classic CTNNB1 morphology.
Graphical Abstract
CTNNB1 mutations were found in 13% of cases, exclusively in exon 3, with mutations at D32-S37, T41 and S45. CTNNB1 mutations correlated strongly with diffuse strong glutamine synthetase (GS) expression, nuclear β-catenin expression and classic CTNNB1 morphology.
Open Research
Data availability
All data generated or analysed during this study are included in this article and its supporting information files. Further enquiries can be directed to the corresponding author.
Supporting Information
| Filename | Description |
|---|---|
| his15363-sup-0001-TableS1.zipZip archive, 66.8 KB |
Table S1: The sequence of primers used for amplification of CTNNB1 gene. Table S2: List of CTNNB1-mutated HBV-related HCC cases. Table S3: Comparison of clinicopathologic characteristics according to CTNNB1 mutation status. Table S4: Comparison of clinicopathologic characteristics according to diffuse strong glutamine synthetase expression. Table S5: Comparison of clinicopathologic characteristics according to nuclear β-catenin expression. Table S6: Comparison of clinicopathologic characteristics according to CTNNB1 morphology. Table S7: Clinicopathological details of HBV-related HCC cases with CTNNB1 mutation (next-generation sequencing cohort). |
| his15363-sup-0002-FigureS1.jpgJPEG image, 106.6 KB |
Figure S1: Recurrence-free survival of hepatocellular carcinoma patients, stratified by CTNNB1 mutation status (A), glutamine synthetase (GS) expression pattern (B), nuclear β-catenin expression status (C) and CTNNB1 morphology (D). |
| his15363-sup-0003-FigureS2.tifTIFF image, 226.6 KB |
Figure S2: CTNNB1 mutation status in HBV-related HCC cases of the next-generation sequencing (NGS) cohort (A, n = 24) and the total cohort (B, n = 132). Frequency of CTNNB1 morphology according to CTNNB1 mutation status (C). Frequency of histological features according to CTNNB1 mutation status (D) (MTM: macrotrabecular massive subtype; VETC: vessels encapsulating tumour clusters pattern). |
| his15363-sup-0004-FigureS3.tifTIFF image, 46.6 KB |
Figure S3: Differences in tumour size (A) and frequencies of macrotrabecular massive (MTM) subtype and vessels encapsulating tumour clusters (VETC) pattern (B) according to the presence of tumour necrosis. |
| his15363-sup-0005-FigureS4.tifTIFF image, 27.5 KB |
Figure S4: Vessels encapsulating tumour clusters (VETC) pattern and macrotrabecular-massive (MTM) subtype according to glutamine synthetase (GS) expression pattern in tissue microarray cohort. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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