Evaluation of tumoral glypican 3 mRNA level as a diagnostic and prognostic biomarker for hepatitis-b virus-associated hepatocellular carcinoma by an integrative transcriptomic meta-analysis and bioinformatics
Abstract
Aim: The aim of this study is to evaluate the potential of GPC3 mRNA level as a diagnostic and prognostic biomarker for HBV-associated HCC.
Materials and Methods: GPC3 mRNA expression in HBV-associated HCC tumor tissues compared to matched adjacent tissues was evaluated by integrative transcriptomic meta-analysis. The results were validated in a different patient cohort and the possible associations between GPC3 mRNA level and the clinical variables were evaluated.
Results: Transcriptomic data of HBV-associated HCC tissues (n=61) and matched adjacent tissues (n=61) from four datasets (GSE19665;GSE84402;GSE121248;GSE55092) were included in the meta-analysis. GPC3 mRNA level was found to be higher in tumors than adjacent tissues (fold change=12.88; p= 0;FDR=0). The result was validated in GSE14520, (HBV-associated HCC(n)=203; matched adjacent tissue(n)=203), (log-fold-change= 4.82; adj.p=1.43E-79). It was found that GPC3 mRNA level could distinguish HCC from adjacent tissues with high specificity and sensitivity (AUC=0.9108;95%CI=0.08792-0.9424;p<0.0001). There was no association between tumoral GPC3 mRNA level and overall survival (HR (logrank)=0.81;95%CI=0.5223-1.2771;p=0.3663), recurrence within 3 years (p=0.5793), and early, or late recurrence (p= 0.9950). Multivariate Cox proportional hazards regression analyzes also found no association between GPC3 mRNA level and overall survival. High GPC3 mRNA level was associated with high serum AFP level, small tumor size and active viral replication. GPC3 mRNA level was higher at stage 1 than CLIP stage 0 but showed no association with TNM and BCLC staging.
Conclusion: The results of the study suggest that the GPC3 mRNA level has the potential to be a diagnostic biomarker that can work with high specificity and sensitivity in differentiating between HBV-associated HCC and adjacent tissues. However, its potential to be a prognostic biomarker is low.
References
- Kim E, Viatour P. Hepatocellular carcinoma: Old friends and new tricks. Experimental & Molecular Medicine 2020; 52: 1898-907.
- Yang H-C, Kao J-H. Persistence of hepatitis b virus covalently closed circular DNA in hepatocytes: Molecular mechanisms and clinical significance. Emerging Microbes & Infections 2014; 3: 1-7.
- Allweiss L, Dandri M. The role of cccdna in hbv maintenance. Viruses 2017; 9: 156.
- Zhou F, Shang W, Yu X, Tian J. Glypican-3: A promising biomarker for hepatocellular carcinoma diagnosis and treatment. 2018; 38: 741-67.
- Anatelli F, Chuang ST, Yang XJ, Wang HL. Value of glypican 3 immunostaining in the diagnosis of hepatocellular carcinoma on needle biopsy. Am J Clin Pathol 2008; 130: 219-23.
- Sharov AA, Schlessinger D, Ko MS. Exatlas: An interactive online tool for meta-analysis of gene expression data. J Bioinform Comput Biol 2015; 13: 1550019.
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- Deng YB, Nagae G, Midorikawa Y, Yagi K, Tsutsumi S, Yamamoto S, et al. Identification of genes preferentially methylated in hepatitis c virus-related hepatocellular carcinoma. Cancer Sci 2010; 101: 1501-10.
- Wang H, Huo X, Yang XR, He J, Cheng L, Wang N, et al. Stat3-mediated upregulation of lncrna hoxd-as1 as a cerna facilitates liver cancer metastasis by regulating sox4. Mol Cancer 2017; 16: 136.
- Wang SM, Ooi LL, Hui KM. Identification and validation of a novel gene signature associated with the recurrence of human hepatocellular carcinoma. Clin Cancer Res 2007; 13: 6275-83.
- Melis M, Diaz G, Kleiner DE, Zamboni F, Kabat J, Lai J, et al. Viral expression and molecular profiling in liver tissue versus microdissected hepatocytes in hepatitis b virus-associated hepatocellular carcinoma. J Transl Med 2014; 12: 230.
- 12. Roessler S, Jia HL, Budhu A, Forgues M, Ye QH, Lee JS, et al. A unique metastasis gene signature enables prediction of tumor relapse in early-stage hepatocellular carcinoma patients. Cancer Res 2010; 70: 10202-12.
- Wang Y-L, Zhu Z-J, Teng D-H, Yao Z, Gao W, Shen Z-Y. Glypican-3 expression and its relationship with recurrence of hcc after liver transplantation. World journal of gastroenterology 2012; 18: 2408-14.
- Maurel M, Jalvy S, Ladeiro Y, Combe C, Vachet L, Sagliocco F, et al. A functional screening identifies five micrornas controlling glypican-3: Role of mir-1271 down-regulation in hepatocellular carcinoma. 2013; 57: 195-204.
- Lü Z-L, Luo D-Z, Wen J-M. Expression and significance of tumor-related genes in hcc. World journal of gastroenterology 2005; 11: 3850-4.
- Pan C, Wang X, Chen W, Tao C, Xu X, Jin L, et al. Reevaluation of glypican-3 as a prognostic marker in hcc using x-tile software. Med Oncol 2015; 32: 359.
- Fu S-J, Qi C-Y, Xiao W-K, Li S-Q, Peng B-G, Liang L-J. Glypican-3 is a potential prognostic biomarker for hepatocellular carcinoma after curative resection. Surgery 2013; 154: 536-44.
- Jeon Y, Kim H, Jang ES, Hong S, Kim JW, Yoon Y-S, et al. Expression profile and prognostic value of glypican-3 in post-operative south korean hepatocellular carcinoma patients. APMIS 2016; 124: 208-15.
- Cui X, Li Z, Gao PJ, Gao J, Zhu JY. Prognostic value of glypican-3 in patients with hbv-associated hepatocellular carcinoma after liver transplantation. Hepatobiliary Pancreat Dis Int 2015; 14: 157-63.
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- Moudi B, Heidari Z, Mahmoudzadeh-Sagheb H. Meta-analysis and systematic review of prognostic significance of glypican-3 in patients with hepatitis b-related hepatocellular carcinoma. Virusdisease 2019; 30: 193-200.
Hepatit-B virüs ilişkili hepatosellüler karsinomda tümöral glipikan 3 mRNA seviyesinin diagnostik ve prognostik biyobelirteç olabilme potansiyelinin entegratif transkriptomik meta-analiz ve biyoinformatik ile değerlendirilmesi
Abstract
Amaç: Bu çalışmanın amacı HBV-ilişkili hepatosellüler kansinom hastalarında tümöral GPC3 mRNA seviyesinin diagnostik ve prognostik biyobelirteç olabilme potansiyelinin değerlendirilmesidir.
Gereç ve Yöntem: Eşlenik tümör içermeyen karaciğer dokularına göre HBV-ilişkili HCC tümör dokularında GPC3 mRNA ekspresyonu entegratif transkriptomik meta-analiz yöntemi ile belirlendi. Sonuçlar farklı bir hasta kohortunda valide edildi ve GPC3 mRNA seviyesi ile klinik değişkenler arasındaki ilişki değerlendirildi.
Bulgular: Meta-analize 4 farklı veri setinden (GSE19665;GSE84402;GSE121248;GSE55092) HBV-ilişkili hepatosellüler karsinom dokuları (n=61) ile eşlenik tümör içermeyen dokulara (n=61) ait transkriptomik veriler dahil edildi. GPC3 mRNA seviyesi’nin eşlenik dokulara göre tümörde daha yüksek olduğu bulundu (kat değişimi=12,88; p=0; FDR=0). Sonuçlar GSE14520 veri setinde (HBV-ilişkili HCC tümör (n)=203;eşlenik non-tümöral doku (n)=203) valide edildi (log-kat değişimi= 4,82; adj.p=1, 43 E-79). ROC analizi sonucunda GPC3 mRNA seviyesinin tümör dokularını tümör içermeyen eşlenik karaciğer dokularından yüksek spesifite ve sensitivite ile ayırabildiği bulundu (n=203;AUC=0,9108;%95CI=0,08792-0,9424;p<0,0001). Tümöral GPC3 mRNA seviyesi ile hastalarda genel sağkalım (HR (logrank)= 0,81; %95CI=0,5223-1,2771; p= 0,3663), 3 yıl içinde rekürrans gelişimi (p=0.5793) ya da erken (<1 yıl) ve geç rekürrans (>3 yıl) (p= 0.9950) arasında bir ilişki bulunmadı. Çok-değişkenli Cox orantılı tehlikeler regresyon analizleri sonucunda da GPC3 mRNA seviyesi ile genel sağkalım arasında bir ilişki bulunmadı. Yüksek GPC3 mRNA seviyesi yüksek serum AFP seviyesi, küçük tümör boyutu ve aktif viral replikasyon ile ilişkili bulundu. GPC3 mRNA seviyesi CLIP evre 0’a göre evre 1’de daha yüksekti, fakat TNM ve BCLC evreleme arasında ilişki yoktu.
Sonuç: Çalışma sonuçları HBV-ilişkili HCC ve yakın tümör içermeyen karaciğer doku ayrımında GPC3 mRNA seviyesinin yüksek spesifite ve sensitivite ile iş görebilecek bir diagnostik biyobelirteç olma potansiyelinin oldukça yüksek, fakat prognostik bir biyobelirteç olabilme potansiyelinin düşük olduğunu önermektedir.
References
- Kim E, Viatour P. Hepatocellular carcinoma: Old friends and new tricks. Experimental & Molecular Medicine 2020; 52: 1898-907.
- Yang H-C, Kao J-H. Persistence of hepatitis b virus covalently closed circular DNA in hepatocytes: Molecular mechanisms and clinical significance. Emerging Microbes & Infections 2014; 3: 1-7.
- Allweiss L, Dandri M. The role of cccdna in hbv maintenance. Viruses 2017; 9: 156.
- Zhou F, Shang W, Yu X, Tian J. Glypican-3: A promising biomarker for hepatocellular carcinoma diagnosis and treatment. 2018; 38: 741-67.
- Anatelli F, Chuang ST, Yang XJ, Wang HL. Value of glypican 3 immunostaining in the diagnosis of hepatocellular carcinoma on needle biopsy. Am J Clin Pathol 2008; 130: 219-23.
- Sharov AA, Schlessinger D, Ko MS. Exatlas: An interactive online tool for meta-analysis of gene expression data. J Bioinform Comput Biol 2015; 13: 1550019.
- Atay S. Integrated transcriptome meta-analysis of pancreatic ductal adenocarcinoma and matched adjacent pancreatic tissues. PeerJ 2020; 8: e10141.
- Deng YB, Nagae G, Midorikawa Y, Yagi K, Tsutsumi S, Yamamoto S, et al. Identification of genes preferentially methylated in hepatitis c virus-related hepatocellular carcinoma. Cancer Sci 2010; 101: 1501-10.
- Wang H, Huo X, Yang XR, He J, Cheng L, Wang N, et al. Stat3-mediated upregulation of lncrna hoxd-as1 as a cerna facilitates liver cancer metastasis by regulating sox4. Mol Cancer 2017; 16: 136.
- Wang SM, Ooi LL, Hui KM. Identification and validation of a novel gene signature associated with the recurrence of human hepatocellular carcinoma. Clin Cancer Res 2007; 13: 6275-83.
- Melis M, Diaz G, Kleiner DE, Zamboni F, Kabat J, Lai J, et al. Viral expression and molecular profiling in liver tissue versus microdissected hepatocytes in hepatitis b virus-associated hepatocellular carcinoma. J Transl Med 2014; 12: 230.
- 12. Roessler S, Jia HL, Budhu A, Forgues M, Ye QH, Lee JS, et al. A unique metastasis gene signature enables prediction of tumor relapse in early-stage hepatocellular carcinoma patients. Cancer Res 2010; 70: 10202-12.
- Wang Y-L, Zhu Z-J, Teng D-H, Yao Z, Gao W, Shen Z-Y. Glypican-3 expression and its relationship with recurrence of hcc after liver transplantation. World journal of gastroenterology 2012; 18: 2408-14.
- Maurel M, Jalvy S, Ladeiro Y, Combe C, Vachet L, Sagliocco F, et al. A functional screening identifies five micrornas controlling glypican-3: Role of mir-1271 down-regulation in hepatocellular carcinoma. 2013; 57: 195-204.
- Lü Z-L, Luo D-Z, Wen J-M. Expression and significance of tumor-related genes in hcc. World journal of gastroenterology 2005; 11: 3850-4.
- Pan C, Wang X, Chen W, Tao C, Xu X, Jin L, et al. Reevaluation of glypican-3 as a prognostic marker in hcc using x-tile software. Med Oncol 2015; 32: 359.
- Fu S-J, Qi C-Y, Xiao W-K, Li S-Q, Peng B-G, Liang L-J. Glypican-3 is a potential prognostic biomarker for hepatocellular carcinoma after curative resection. Surgery 2013; 154: 536-44.
- Jeon Y, Kim H, Jang ES, Hong S, Kim JW, Yoon Y-S, et al. Expression profile and prognostic value of glypican-3 in post-operative south korean hepatocellular carcinoma patients. APMIS 2016; 124: 208-15.
- Cui X, Li Z, Gao PJ, Gao J, Zhu JY. Prognostic value of glypican-3 in patients with hbv-associated hepatocellular carcinoma after liver transplantation. Hepatobiliary Pancreat Dis Int 2015; 14: 157-63.
- Ning S, Bin C, Na H, Peng S, Yi D, Xiang-hua Y, et al. Glypican-3, a novel prognostic marker of hepatocellular cancer, is related with postoperative metastasis and recurrence in hepatocellular cancer patients. Molecular Biology Reports 2012; 39: 351-7.
- Liang J, Ding T, Guo ZW, Yu XJ, Hu YZ, Zheng L, Xu J. Expression pattern of tumour-associated antigens in hepatocellular carcinoma: Association with immune infiltration and disease progression. British journal of cancer 2013; 109: 1031-9.
- Moudi B, Heidari Z, Mahmoudzadeh-Sagheb H. Meta-analysis and systematic review of prognostic significance of glypican-3 in patients with hepatitis b-related hepatocellular carcinoma. Virusdisease 2019; 30: 193-200.
Details
| Primary Language | Turkish |
|---|---|
| Subjects | Health Care Administration |
| Journal Section | Research Articles |
| Authors | |
| Publication Date | June 13, 2022 |
| Submission Date | August 31, 2021 |
| Published in Issue | Year 2022 |