The role of ERCC1 and AFP gene polymorphism in hepatocellular carcinoma.
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ABSTRACT:
SUBMITTER: Huang YL
PROVIDER: S-EPMC6456153 | biostudies-literature | 2019 Apr
REPOSITORIES: biostudies-literature
Publications
The role of ERCC1 and AFP gene polymorphism in hepatocellular carcinoma.
Huang Yu-Liang YL Wu Jun-Rong JR Fang Min M Zhao Hui-Liu HL Liu Zhi-Min ZM Ye Jian J Huang Ling-Sha LS Zhu Bo B
Medicine 20190401 14
The aim of this study was to evaluate the effects of polymorphisms in excision repair cross-complementation group 1 (ERCC1) and alpha-fetoprotein (AFP) genes and their haplotypes on the susceptibility to hepatocellular carcinoma (HCC), and to decipher the association between single-nucleotide polymorphisms (SNPs) and clinicopathologic characteristics of HCC.Peripheral blood DNA was extracted from 206 subjects. SNaPshot technique was used for genotyping 5 SNP sites of the ERCC1 rs735482, rs104628 ...[more]
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Project description:Alpha-fetoprotein (AFP), Lens culinaris-agglutinin-reactive fraction of AFP (AFP-L3), and protein induced by vitamin K absence or antagonist-II (PIVKA-II) are widely used as tumor markers for the diagnosis of hepatocellular carcinoma (HCC). This study compared the diagnostic values of AFP, AFP-L3, and PIVKA-II individually and in combination to find the best biomarker or biomarker panel.Seventy-nine patients with newly diagnosed HCC and 77 non-HCC control patients with liver cirrhosis were enrolled. AFP, AFP-L3, and PIVKA-II were measured in the same serum samples using microchip capillary electrophoresis and a liquid-phase binding assay on an automatic analyzer. Receiver-operating characteristic curve analyses were also applied to all combinations of the markers.When the 3 biomarkers were analyzed individually, AFP showed the largest area under the receiver-operating characteristic curve (AUC) (0.751). For combinations of the biomarkers, the AUC was highest (0.765) for "PIVKA-II > 40 mAU/mL and AFP > 10 ng/mL." The combination of "PIVKA-II > 40 mAU/mL and AFP > 10 ng/mL and AFP-L3 > 10%" had worse sensitivity and lower AUC (P = 0.001). The highest AUC of a single biomarker was highest for AFP and of a combination was "PIVKA-II > 40 mAU/mL and AFP > 10 ng/mL," with this also being the case when the cut-off value of AFP and AFP-L3 was changed.Alpha-fetoprotein showed the best diagnostic performance as a single biomarker for HCC. The diagnostic value of AFP was improved by combining it with PIVKA-II, but adding AFP-L3 did not contribute to the ability to distinguish between HCC and non-HCC liver cirrhosis. These findings were not altered when the cut-off value of AFP and AFP-L3 was changed.
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Project description:BackgroundSerum lens culinaris agglutinin-reactive fraction of α-fetoprotein (AFP-L3%) has been widely used for HCC diagnosis and follow-up surveillance as tumor serologic marker. However, the prognostic value of high pre-treatment serum AFP-L3% in patients with hepatocellular carcinoma (HCC) remains controversial. We therefore conduct a meta-analysis to assess the relationship between high pre-treatment serum AFP-L3% and clinical outcome of HCC.MethodsEligible studies were identified through systematic literature searches. A meta-analysis of fifteen studies (4,465 patients) was carried out to evaluate the association between high pre-treatment serum AFP-L3% and overall survival (OS) and disease-free survival (DFS) in HCC patients. Sensitivity and subgroup analyses were also conducted in this meta-analysis.ResultsOur analysis results showed that high pre-treatment serum AFP-L3% implied poor OS (HR: 1.65, 95%CI: 1.45-1.89 p<0.00001) and DFS (HR: 1.80, 95% CI: 1.49-2.17 p<0.00001) of HCC. Subgroup analysis revealed that there was association between pre-treatment serum AFP-L3% and endpoint (OS and DFS) in low AFP concentration HCC patients (HR: 1.96, 95% CI: 1.24-3.10, p = 0.004; HR: 2.53, 95% CI: 1.09-5.89, p = 0.03, respectively).ConclusionThe current evidence suggests that high pre-treatment serum AFP-L3% levels indicated a poor prognosis for patients with HCC and AFP-L3% may have significant prognostic value in HCC patients with low AFP concentration.
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Project description:Background & aimsHepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) is prevalent worldwide. Despite its limitations, serum alpha-fetoprotein (AFP) remains the most widely-used biomarker for the diagnosis of HCC. This study aimed to assess whether measurement of peripheral plasma Dickkopf-1 (DKK1) and Tie2-expressing monocytes (TEMs) could overcome the limitations of AFP and improve the diagnostic accuracy of HCC.MethodsPlasma DKK1 level and the percentage of TEMs in peripheral CD14+CD16+ monocytes from HCC patients (n = 82), HBV-related liver cirrhosis (LC) patients (n = 29), chronic hepatitis B (CHB) infected patients (n = 28) and healthy volunteers (n = 31) were analyzed by ELISA and flow cytometry. Receiver operating characteristic (ROC) curves were used to analyze a single biomarker, or a combination of two or three biomarkers. Univariate and multivariate analyses were performed to assess the significance of each marker in prediction of HCC and AFP-negative HCC from LC patients.ResultsThe percentage of TEMs in peripheral CD14+CD16+ monocytes and plasma level of DKK1 in HCC group were significantly higher than those in LC, CHB and healthy control groups (all P-values <0.05). The percentage of TEMs alone was also significantly higher in AFP-negative HCC group than that in LC, CHB and healthy control groups (all P-values <0.05). Plasma DKK1 level alone could not distinguish between AFP-negative HCC and LC patients. ROC curves showed that the optimal diagnostic cutoff value was 550.93 ng/L for DKK1 and 4.95% for TEMs. There was no significant difference in AUC of DKK1, TEMs and AFP in HCC diagnosis between the four groups (all P>0.05). A combination of DKK1, TEMs and AFP measurements increased the AUC for HCC diagnosis as compared with either marker alone (0.833; 95%CI 0.768-0.886). The AUC for TEMs was 0.692 (95% CI 0.564-0.819) in differentiating AFP-negative HCC from LC, with a sensitivity of 80.0% and a specificity of 65.52%. Only TEMs prevailed as a significant predictor for AFP-negative HCC differentiating from LC patients in univariate and multivariate analyses (P = 0.016, P = 0.023).ConclusionsTEMs and DKK1 may prove to be potential complementary biomarkers for AFP in the diagnosis of HCC. TEMs rather than DKK1 could serve as a complementary biomarker for AFP in the differential diagnosis of AFP-negative HCC versus LC patients.
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Project description:Excision repair cross?complementing rodent repair deficiency, complementation group 5 (ERCC5, XPG) is a key molecule in DNA damage repair. We analyzed the contribution of ERCC5 rs751402 polymorphism in increased susceptibility to hepatocellular carcinoma (HCC). A total of 96 patients diagnosed with HCC and 336 healthy controls provided blood samples for analysis of rs751402 genotypes. Demographic data and information on habitual use of tobacco and alcohol were collected. After adjusting for covariates, rs751402 homozygocity for allele C was found to confer a statistically significant protection [adjusted odds ratio (AOR)=0.56; 95% CI, 0.35?0.89; p=0.01] against HCC, whereas rs751402 T alleles were associated with increased risk (AOR=1.69; 95% CI, 0.74?3.87). Individuals with the inherited ERCC rs751402 CC genotype may experience significant protection against HCC, whereas individuals with T alleles appear to be exposed to higher risk.
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Project description:The role of α-fetoprotein (AFP) in the surveillance and diagnosis of hepatocellular carcinoma (HCC) has been questioned in recent years due to its low sensitivity and specificity. In addition to AFP, several new serum biomarkers, such as lens culinaris agglutinin-reactive fraction of AFP (AFP-L3) and des-gamma-carboxy prothrombin (DCP), have also been identified as useful HCC serological markers. However, the exact diagnostic value of the combinations of these biomarkers for detecting HCC in patients with liver disease remains unclear. Thus, we performed the current meta-analysis to assess performance of AFP+AFP-L3%+DCP for diagnosing HCC. Studies were systematically searched in PubMed, Embase, the Cochrane Library, CNKI, and WanFang Data databases. After full-text evaluation, 13 studies from 11 articles focusing on the combination of the three serum biomarkers for HCC detection were enrolled. Random-effects models were used due to the presence of heterogeneity. The pooled sensitivity and specificity for AFP+AFP-L3%+DCP were 88% and 79%, respectively. The area under the summary receiver operating characteristic (sROC) curve was 0.91, and the diagnostic odds ratio (DOR) was 28.33 (95% CI 16.78-47.83). Subgroup analysis showed that the pooled sensitivity and specificity of AFP+AFP-L3%+DCP in the diagnosis of HCC versus cirrhosis patients were 0.81 and 0.82, respectively. In conclusion, the combination of AFP, AFP-L3%, and DCP may prove to be useful in the diagnosis and screening of HCC.
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Project description:Background Serum tumor markers are ubiquitously used in the clinic for cancer screening. However, the mechanisms accounting for the elevated levels of the serum tumor markers remain to be explored. Methods We performed a pan-cancer analysis of serum alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA) and prostate-specific antigen (PSA). The relation between concentration of serum tumor markers and the expression of their coding genes was assessed. Then the expression of AFP and its genomic background in hepatocellular carcinoma (liver cancer) was studied. Results High expression of AFP mRNA was found mainly in liver cancer. In gastric cancer, breast cancer and lung cancer, high AFP mRNA expression was also discovered occasionally. In liver cancer patients, serum AFP levels correlated significantly with AFP mRNA expression in cancer tissues (r = 0.72, p = 1.6e-45). Whole transcriptome analysis revealed that serum AFP levels clearly separated liver cancer into two classes with distinct expression profiles according to PCA analysis. Gene co-expression analysis revealed that AFP expression was connected to a module enriched with genes accounting for cell cycle and cell proliferation regulation. In addition, high AFP expression was associated with the molecular classification of liver cancer, including iCluster (Chi-square: 16.86, P = 0.0002). Methylation analysis revealed de-methylation of AFP promoter occurred in some liver cancer tissues, which was significantly related to AFP mRNA expression. Survival analysis indicated high serum AFP levels was prognostic of poorer survival of the liver cancer patients (Log-rank test: p = 0.046). This was confirmed by an independent dataset in which liver cancer patients with high serum AFP also had poorer survival (Log-rank test: p = 0.024). Conclusion High expression of AFP defined a subtype of liver cancer with distinct gene expression profiles and clinical features. De-methylation of cytosine from CpG di-nucleotides in AFP promoter may be the cause of AFP re-expression in adult human liver cancer tissue.
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Project description:Background and Aim: Alpha-fetoprotein (AFP), a lens culinaris agglutinin-reactive fraction of AFP (AFP-L3), is a protein that is induced by vitamin K deficiency or antagonist-II (PIVKA-II) that has been clinically used as a serum biomarker for early detection and diagnosis of hepatocellular carcinoma (HCC). Diagnostic performance of each serum biomarker alone, or their combinations for the detection of hepatitis C virus (HCV)-associated HCC were compared. Methods: Serum AFP, AFP-L3, and PIVKA-II levels were evaluated in patients with HCV-associated HCC, and those with chronic HCV infection without HCC (HCV-controls). The areas under the curve (AUC), sensitivity, and specificity were compared to identify the diagnostic performance of each serum HCC biomarker alone or in combination. Results: Overall, 172 HCV controls and 105 patients with HCV-associated HCC were enrolled. The AFP, AFP-L3, and PIVKA-II levels were significantly increased among patients with HCV-associated HCC when compared with HCV patients without HCC (p < 0.001). When these biomarkers were analyzed individually, PIVKA-II revealed the best predictive performance (AUC: PIVKA-II 0.90 vs. AFP 0.80 vs. AFP-L3 0.69, p < 0.001). In evaluating the combinations of any two biomarkers, the best predictive performance was found in PIVKA-II + AFP (0.93 vs. AFP + AFP-L3 0.78, p = 0.001; and PIVKA-II + AFP-L3 0.89, p < 0.001), which had no difference compared to the predictive performance of the combination of all three serum biomarkers (AFP + AFP-L3 + PIVKA-II 0.93, p = 0.277). Similar results were identified in the subgroups of patients with HCV-induced cirrhosis, and among patients with early-stage HCC defined by BCLC and TNM staging. Conclusions: The addition of the PIVKA-II test to routine AFP test maybe provide a more suitable biomarker approach to detect HCV-induced HCC in patients with HCV infection undergoing HCC surveillance.
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