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Transcriptome analysis identifies metallothionein as biomarkers to predict recurrence in hepatocellular cacinoma.

ABSTRACT: BACKGROUND:Liver cancer is the fifth most common cancer, and hepatocellular carcinoma (HCC) is the major liver tumor type seen in adults. HCC is usually caused by chronic liver disease such as hepatitis B virus or hepatitis C virus infection. One of the promising treatments for HCC is liver transplantation, in which a diseased liver is replaced with a healthy liver from another person. However, recurrence of HCC after surgery is a significant problem. Therefore, it is important to discover reliable cellular biomarkers that can predict recurrence in HCC. METHODS:We analyzed previously published HCC RNA-Seq data that includes 21 paired tumor and normal samples, in which nine tumors were recurrent after orthotopic liver transplantation and 12 were nonrecurrent tumors with their paired normal samples. We used both the reference genome and de novo transcriptome assembly based analyses to identify differentially expressed genes (DEG) and used RandomForest to discover biomarkers. RESULTS:We obtained 398 DEG using the Reference approach and 412 DEG using de novo assembly approach. Among these DEG, 258 genes were identified by both approaches. We further identified 30 biomarkers that could predict the recurrence. We used another independent HCC study that includes 50 patients normal and tumor samples. By using these 30 biomarkers, the prediction accuracy was 100% for normal condition and 98% for tumor condition. A group of Metallothionein was specifically discovered as biomarkers in both reference and de novo assembly approaches. CONCLUSION:We identified a group of Metallothionein genes as biomarkers to predict recurrence. The metallothionein genes were all down-regulated in tumor samples, suggesting that low metallothionein expression may be a promoter of tumor growth. In addition, using de novo assembly identified some unique biomarkers, further confirmed the necessity of conducting a de novo assembly in human cancer study.

SUBMITTER: Wang S

PROVIDER: S-EPMC6565558 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Transcriptome analysis identifies metallothionein as biomarkers to predict recurrence in hepatocellular cacinoma.

Wang Sufang S Gribskov Michael M

Molecular genetics & genomic medicine 20190506 6

<h4>Background</h4>Liver cancer is the fifth most common cancer, and hepatocellular carcinoma (HCC) is the major liver tumor type seen in adults. HCC is usually caused by chronic liver disease such as hepatitis B virus or hepatitis C virus infection. One of the promising treatments for HCC is liver transplantation, in which a diseased liver is replaced with a healthy liver from another person. However, recurrence of HCC after surgery is a significant problem. Therefore, it is important to discov ...[more]

PMID: 31056863

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Project description:BackgroundCopper (Cu) and zinc (Zn) are essential nutrients and cofactors of enzymatic reactions with their binding partner. Metallothionein (MT) plays an important role in protecting against heavy metals and oxidative injury, however it may also portend drug resistance and a worse prognosis for hepatocellular carcinoma (HCC) patients. The aim of this study was to determine the amount of Cu, Zn, Cu/Zn and MT in evaluating a group of patients with HCC, including those treated with lenvatinib.MethodsWe enrolled 175 patients with HCC (139 men, 36 women; mean age 71.1 years; hepatitis C virus n = 85, hepatitis B virus n = 19, hepatitis C virus and hepatitis B virus n = 2, non-alcoholic steatohepatitis n = 39, alcohol n = 25, others n = 5; Child-Pugh A n = 141, Child-Pugh B n = 30, Child-Pugh C n = 4; Barcelona clinic liver cancer (BCLC) stage 0 n = 38, stage A n = 56, stage B n = 39, stage C n = 38, stage D n = 4). We evaluated the associations between Cu, Zn and MT. The study outcome was liver cancer-specific survival. Moreover, we treated 12 HCC patients with lenvatinib and investigated the changes in MT during lenvatinib therapy.ResultsThe serum level of Cu was positively correlated with alanine aminotransferase and the BCLC stage. The serum level of Zn decreased concordant with liver disease progression. Patients with a Cu/Zn ratio≥0.999 had significantly improved rates of survival when compared to patients with a Cu/Zn ratio<0.999 (45.3 vs. 30.1 months, p<0.001). MT was significantly correlated with the Cu/Zn ratio and increased after the administration of lenvatinib. Using multivariate Cox regression analyses, it was determined that the Cu/Zn ratio (hazard ratio [HR]: 1.442, p = 0.008), alpha-fetoprotein (HR: 1.000, p<0.001) and BCLC stage (HR: 2.087, p<0.001) were independent predictors of survival.ConclusionsThe Cu/Zn ratio could serve as a useful predictive marker for survival in cases of HCC. MT levels increased in HCC patients receiving lenvatinib therapy, and maybe a predictor of reduced survival.

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Transcriptome analysis identifies metallothionein as biomarkers to predict recurrence in hepatocellular cacinoma.

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Transcriptome analysis identifies metallothionein as biomarkers to predict recurrence in hepatocellular cacinoma.

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