Identification of Platform-Independent Diagnostic Biomarker Panel for Hepatocellular Carcinoma Using Large-Scale Transcriptomics Data

AbstractThe high mortality rate of hepatocellular carcinoma (HCC) is primarily due to its late diagnosis. In the past numerous attempts have been made to design genetic biomarkers for the identification of HCC; unfortunately, most of the studies are based on a small dataset obtained from a specific platform or lack of their reasonable validation performance on the external datasets. In order to identify a universal expression-based diagnostic biomarker panel for HCC that can be applicable across multiple platforms; we have employed large scale transcriptomic profiling datasets containing a total of 2,306 HCC and 1,655 non-tumorous tissue samples. These samples were obtained from 29 studies generated by mainly four types of profiling techniques include Affymetrix, Illumina, Agilent and High-throughput-seq, which implemented a wide range of platforms. Firstly, we scrutinized 26 genes that are differentially expressed or regulated in uniform pattern among numerous datasets. Subsequently, we identified three genes (FCN3, CLEC1B, & PRC1) panel-based HCC biomarker using different machine learning techniques include Simple-threshold based approach, Extra Trees, Support Vector Machine, Random Forest, K Neighbors Classifier, Logistic Regression etc. Three-genes panel-based HCC biomarker classified HCC samples and non-tumorous samples of training and three external validation datasets with an accuracy between 93 to 98% and AUROC (Area Under Receiver Operating Characteristic curve) in a range of 0.97 to 1.0. Furthermore, the prognostic potential of these genes was evaluated on TCGA cohort and GSE14520 cohort using univariate survival analysis revealed that these genes are independent prognostic indicators for various types of the survivals, i.e. OS (Overall Survival), PFS (Progression-Free Survival), DFS/RFS (Disease-Free Survival/Recurrence-Free Survival) and DSS (Disease-Specific Survival) of HCC patients and significantly stratify high-risk and low-risk HCC patients (p-value <0.05). In conclusion, we identified a universal platform-independent three genes-based biomarker that can predict HCC patients with high precision; also possess significant prognostic potential. Eventually, to provide service to the scientific community, we developed a webserver HCCPred based on the above study (http://webs.iiitd.edu.in/raghava/hccpred/).

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EZ-ALBI Score for Predicting Hepatocellular Carcinoma Prognosis

Liver Cancer ◽

10.1159/000508971 ◽

2020 ◽

Vol 9 (6) ◽

pp. 734-743

Author(s):

Kazuya Kariyama ◽

Kazuhiro Nouso ◽

Atsushi Hiraoka ◽

Akiko Wakuta ◽

Ayano Oonishi ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Function ◽

Large Scale ◽

Regression Coefficient ◽

Information Criterion ◽

Proportional Hazard ◽

Cox Proportional Hazard ◽

Highly Correlated ◽

Survival Risk ◽

Good Agreement

Introduction: The ALBI score is acknowledged as the gold standard for the assessment of liver function in patients with hepatocellular carcinoma (HCC). Unlike the Child-Pugh score, the ALBI score uses only objective parameters, albumin (Alb) and total bilirubin (T.Bil), enabling a better evaluation. However, the complex calculation of the ALBI score limits its applicability. Therefore, we developed a simplified ALBI score, based on data from a large-scale HCC database.We used the data of 5,249 naïve HCC cases registered in eight collaborating hospitals. Methods: We developed a new score, the EZ (Easy)-ALBI score, based on regression coefficients of Alb and T.Bil for survival risk in a multivariate Cox proportional hazard model. We also developed the EZ-ALBI grade and EZ-ALBI-T grade as alternative options for the ALBI grade and ALBI-T grade and evaluated their stratifying ability. Results: The equation used to calculate the EZ-ALBI score was simple {[T.Bil (mg/dL)] – [9 × Alb (g/dL)]}; this value highly correlated with the ALBI score (correlation coefficient, 0.981; p < 0.0001). The correlation was preserved across different Barcelona clinic liver cancer grade scores (regression coefficient, 0.93–0.98) and across different hospitals (regression coefficient, 0.98–0.99), indicating good generalizability. Although a good agreement was observed between ALBI and EZ-ALBI, discrepancies were observed in patients with poor liver function (T.Bil, ≥3 mg/dL; regression coefficient, 0.877). The stratifying ability of EZ-ALBI grade and EZ-ALBI-T grade were good and their Akaike’s information criterion values (35,897 and 34,812, respectively) were comparable with those of ALBI grade and ALBI-T grade (35,914 and 34,816, respectively). Conclusions: The EZ-ALBI score, EZ-ALBI grade, and EZ-ALBI-T grade are useful, simple scores, which might replace the conventional ALBI score in the future.

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N‐glycan fingerprint predicts alpha‐fetoprotein negative hepatocellular carcinoma: a large‐scale multicenter study

International Journal of Cancer ◽

10.1002/ijc.33564 ◽

2021 ◽

Author(s):

Chenjun Huang ◽

Meng Fang ◽

Huijuan Feng ◽

Lijuan Liu ◽

Ya Li ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Multicenter Study ◽

Large Scale ◽

Alpha Fetoprotein

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Diagnostic Evaluation of Des-Gamma-Carboxy Prothrombin versus α-Fetoprotein for Hepatitis B Virus-Related Hepatocellular Carcinoma in China: A Large-Scale, Multicentre Study

PLoS ONE ◽

10.1371/journal.pone.0153227 ◽

2016 ◽

Vol 11 (4) ◽

pp. e0153227 ◽

Cited By ~ 30

Author(s):

Jun Ji ◽

Hao Wang ◽

Yan Li ◽

Lei Zheng ◽

Yuepeng Yin ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Multicentre Study ◽

Large Scale ◽

Diagnostic Evaluation ◽

B Virus

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miR-3677-3p promotes hepatocellular carcinoma progression via inhibiting GSK3β

Acta Biochimica et Biophysica Sinica ◽

10.1093/abbs/gmaa125 ◽

2020 ◽

Vol 52 (12) ◽

pp. 1404-1412

Author(s):

Yanfei Li ◽

Yajie Zhou ◽

Linlin Ma ◽

Dingsheng Liu ◽

Zhensheng Dai ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Proliferation ◽

Untranslated Region ◽

Molecular Mechanisms ◽

Glycogen Synthase ◽

Glycogen Synthase Kinase 3 ◽

Diagnostic Biomarker ◽

Tumor Tissues ◽

Suppress Cell Proliferation ◽

Hcc Cells

Abstract MicroRNAs play important roles in regulating hepatocellular carcinoma (HCC) formation, progression and metastasis. However, their functions and the underlying molecular mechanisms are still unclear. Here, we found that miR-3677-3p was highly expressed in primary tumor tissues of HCC patients. And its inhibition by using sponge in HCC cells could suppress cell proliferation significantly, but it has no effect on cell apoptosis. Through directly targeting to the 3′ untranslated region of glycogen synthase kinase 3-β (GSK3β), miR-3677-3p could inhibit GSK3β expression. Our study revealed that the miR-3677-3p/GSK3β axis may play a crucial role in HCC and miR-3677-3p may serve as a potential diagnostic biomarker or a therapeutic target for HCC.

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Meta-analysis of gene expression for development and validation of a diagnostic biomarker panel for Oral Squamous Cell Carcinoma

Computational Biology and Chemistry ◽

10.1016/j.compbiolchem.2019.06.008 ◽

2019 ◽

Vol 82 ◽

pp. 74-79

Author(s):

Vladimir Makarov ◽

Alex Gorlin

Keyword(s):

Gene Expression ◽

Squamous Cell Carcinoma ◽

Oral Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Meta Analysis ◽

Diagnostic Biomarker ◽

Biomarker Panel ◽

Development And Validation

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Sarcopenia and intramuscular fat deposition are associated with poor survival in Indonesian patients with hepatocellular carcinoma: a retrospective study

10.21203/rs.2.15707/v2 ◽

2019 ◽

Author(s):

Yan Mardian ◽

Yoshihiko Yano ◽

Neneng Ratnasari ◽

Lina Choridah ◽

Widya Wasityastuti ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Large Scale ◽

Cox Regression ◽

Clinical Laboratory ◽

Multivariable Analysis ◽

Lumbar Vertebra ◽

Intramuscular Fat ◽

Skeletal Muscle Index ◽

Computed Tomography Images ◽

Jis Score

Abstract Background A large-scale Japanese study showed that low skeletal muscle index (SMI) and intramuscular fat (IMF) deposition are associated with hepatocellular carcinoma (HCC) survival. Here, we evaluated the effects of SMI and IMF on the survival of Indonesian HCC patients, whose characteristics differ from those of Japanese patients.Methods SMI and mean muscle attenuation (MA) were evaluated using computed tomography images of the third lumbar vertebra (L3) in a prospective cohort of 100 Indonesian HCC patients. Clinical, laboratory and body composition data were analysed using the Kaplan–Meier method and Cox regression model to investigate which factors are associated with prognosis.Results Of 100 patients, 31 were diagnosed with sarcopenia (L3 SMI value ≤36.2 cm 2 /m 2 for men and ≤29.6 cm 2 /m 2 for women), and 65 had IMF deposition (MA value ≤44.4 HU for men and ≤39.3 HU for women). These groups had shorter median survival than the reference groups (both P <0.0001). In multivariable analysis, sarcopenia (hazard ratio [HR], 1.921; P = 0.016), IMF deposition (HR, 3.580; P <0.001), Barcelona Clinic Liver Cancer (BCLC) stages C and D (HR: 2.396, P <0.01 and HR: 6.131, P <0.01, respectively), Japan Integrated Staging (JIS) score 4 (HR: 2.067, P = 0.020), and male gender (HR: 3.211, P <0.001) were independently associated with mortality.Conclusion Sarcopenia and IMF deposition showed superior value in combination with BCLC stage and JIS score for predicting the survival of Indonesian HCC patients. Increased awareness and strategies to prevent or reverse these factors might improve patient outcomes. (Electric word counts: 249)

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