Dataset Information

Plasma and tumoral glypican-3 levels are correlated in patients with hepatitis C virus-related hepatocellular carcinoma.

ABSTRACT: Glypican-3 (GPC3) is a cancer antigen expressed in approximately 80% of hepatocellular carcinomas (HCC) and is secreted into the blood. To confirm the effectiveness of GPC3 as a biomarker in HCC, we analyzed the relationship between GPC3 expression levels in cancer cells and in blood in 56 patients with HCC. Preoperative plasma GPC3 levels were determined with an immunoassay, and expression of GPC3 in resected tumors was analyzed by immunohistochemical staining. Median plasma GPC3 level in all HCC cases was 4.6 pg/mL, and tended to be higher in patients with hepatitis C virus (HCV)-related HCC (HCV group) (9.9 pg/mL) than in patients with hepatitis B virus (HBV)-related HCC (HBV group) (2.6 pg/mL) or in those without virus infection (None group) (3.0 pg/mL), suggesting that the virus type most likely influences GPC3 secretion. Median percentage of GPC3⁺ cells in tumors was also higher in the HCV (26.2%) and HBV (11.1%) groups than in the None group (4.2%). In the HCV group, there was a positive correlation between the two parameters (r = 0.66, P < .01). Moreover, receiver operating characteristic analysis predicted >10% GPC3⁺ cells in a tumor if the cut-off value was 6.8 pg/mL (sensitivity 80%, specificity 100%; area under the curve 0.875, 95% confidence interval 0.726-1) in the HCV group. Plasma concentration of GPC3 could be a predictive marker of tumoral GPC3 expression in patients with HCV-related HCC, suggesting a useful biomarker for immunotherapies targeting GPC3, although larger-scale validations are needed.

SUBMITTER: Shimizu Y

PROVIDER: S-EPMC7004540 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Plasma and tumoral glypican-3 levels are correlated in patients with hepatitis C virus-related hepatocellular carcinoma.

Shimizu Yasuhiro Y Mizuno Shoichi S Fujinami Norihiro N Suzuki Toshihiro T Saito Keigo K Konishi Masaru M Takahashi Shinichiro S Gotohda Naoto N Tada Toshifumi T Toyoda Hidenori H Kumada Takashi T Miura Masahiro M Suto Kouzou K Yamaji Taiki T Matsuda Takahisa T Endo Itaru I Nakatsura Tetsuya T

Cancer science 20191228 2

Glypican-3 (GPC3) is a cancer antigen expressed in approximately 80% of hepatocellular carcinomas (HCC) and is secreted into the blood. To confirm the effectiveness of GPC3 as a biomarker in HCC, we analyzed the relationship between GPC3 expression levels in cancer cells and in blood in 56 patients with HCC. Preoperative plasma GPC3 levels were determined with an immunoassay, and expression of GPC3 in resected tumors was analyzed by immunohistochemical staining. Median plasma GPC3 level in all H ...[more]

PMID: 31774932

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Project description:BackgroundLiver cancer is the sixth most common cancer worldwide and the third leading cause of cancer-related death. As a chronic liver disease, many studies have shown that the immune response plays a key role in the progression of liver cancer. Chronic hepatitis B virus (HBV) infection is one of the high-risk factors for HCC, accounting for 50%-80% of HCC cases worldwide, and little is known about the immune status of HBV associated hepatocellular carcinoma (HBV-HCC), therefore, we aimed to explore the changes in peripheral immunity in patients with HBV-HCC.MethodsIn this study, patients with HBV-HCC (n=26), patients with hepatitis B-related cirrhosis (HBV-LC) (n=31) and healthy volunteers (n=49) were included. The lymphocytes and their subpopulation phenotypes in peripheral blood were characterized. In addition, we explored the effect of viral replication on peripheral immunity in patients with HCC and analyzed the circulating immunophenotypic characteristics at different stages of HCC with flow cytometry.ResultsFirstly, our results showed that the percentages of total αβ T cells in the peripheral blood of HBV-HCC patients was significantly decreased compared to healthy subjects. Secondly, we found that naïve CD4+ T cells in HBV-HCC patients were significantly reduced, terminally differentiated CD8+ T cells, homing memory CD8+ T cells and Th2 cells were increased in peripheral circulation in HBV-HCC patients. Moreover, in the peripheral blood of HBV-HCC patients, expression of TIGIT on CD4+ T cells and PD-1 on the surface of Vδ 1 T cells was increased. In addition, we found that sustained viral replication resulted in up-regulation of TIM3 expression on CD4+ T cells, and TIM3+ γδ T cells increased in peripheral circulation in patients with advanced HBV-HCC.ConclusionOur study showed that circulating lymphocytes in HBV-HCC patients exhibited features of immune exhaustion, especially in HCC patients with persistent viral replication and in patients with intermediate and advanced HBV-HCC, including decreased frequency of T cells and elevated expression of inhibitory receptors including TIGIT and TIM3 on CD4+ T cells and γδ T cells. Meanwhile, our research suggests that the combination of CD3+ T cell and CD8+HLADR+CD38+ T cell may be a potential diagnostic indicator for HBV-HCC. These findings could help us to better understand the immune characteristics of HBV-HCC and explore the immune mechanisms and immunotherapy strategies for HBV-HCC.

Project description:Chronic infections by hepatitis B virus (HBV) and hepatitis C virus (HCV) appear to be the most significant causes of hepatocellular carcinoma (HCC). Aberrant promoter methylation is known to be deeply involved in cancer, including HCC. In this study, we analyzed aberrant promoter methylation on genome-wide scale in 6 HCCs including 3 HBV-related and 3 HCV-related HCCs, 6 matched noncancerous liver tissues and 3 normal liver tissues by methylated DNA immunoprecipitation-on-chip analysis. Candidate genes with promoter methylation were detected more frequently in HCV-related HCC. Candidate genes methylated preferentially to HBV-related or HCV-related HCCs were detected and selected, and methylation levels of the selected genes were validated using 125 liver tissue samples, including 61 HCCs (28 HBV-related HCCs and 33 HCV-related HCCs) and matched 59 matched noncancerous livers, and 5 normal livers, by quantitative methylation analysis using MALDI-TOF mass spectrometry. Among analyzed genes, preferential methylation in HBV-related HCC was validated in 1 gene only. However, 15 genes were found methylated preferentially in HCV-related HCC, which was independent from age. Hierarchical clustering of HCC using these 15 genes stratified HCV-related HCC as a cluster of frequently methylated samples. The 15 genes included genes inhibitory to cancer-related signaling such as RAS/RAF/ERK and Wnt/b-catenin pathways. It was indicated that genes methylated preferentially in HCV-related HCC exist, and it was suggested that DNA methylation might play an important role in HCV-related HCC by silencing cancer-related pathway inhibitors. we analyzed aberrant promoter methylation in 6 HCC clinical samples (including 3 HBV-related HCCs and 3 HCV-related HCCs) and their matched noncancerous tissues on genome-wide scale by the method. Candidate regions of promoter methylation preferentially to HBV-related HCC and HCV-related HCC were selected, and the methylation levels of these genes were measured quantitatively using MALDI-TOF mass spectrometry. Expression levels of these 6 pairs of HCC and 4 more pairs of HCCs and surrounding noncancerous tissues were analyzed by expression array and are reported in this Series. <br><br>This experiment was reloaded in November 2010 after additional curation. this dataset is part of the TransQST collection.

Project description:Background and aimsHepatocellular carcinoma (HCC), which is prevalent worldwide and has a high mortality rate, needs to be effectively diagnosed. We aimed to evaluate the significance of plasma microRNA-15a/16-1 (miR-15a/16) as a biomarker of hepatitis B virus-related HCC (HBV-HCC) using the machine learning model. This study was the first large-scale investigation of these two miRNAs in HCC plasma samples.MethodsUsing quantitative polymerase chain reaction, we measured the plasma miR-15a/16 levels in a total of 766 participants, including 74 healthy controls, 335 with chronic hepatitis B (CHB), 47 with compensated liver cirrhosis, and 310 with HBV-HCC. The diagnostic performance of miR-15a/16 was examined using a machine learning model and compared with that of alpha-fetoprotein (AFP). Lastly, to validate the diagnostic efficiency of miR-15a/16, we performed pseudotemporal sorting of the samples to simulate progression from CHB to HCC.ResultsPlasma miR-15a/16 was significantly decreased in HCC than in all control groups (P < 0.05 for all). In the training cohort, the area under the receiver operating characteristic curve (AUC), sensitivity, and average precision (AP) for the detection of HCC were higher for miR-15a (AUC = 0.80, 67.3%, AP = 0.80) and miR-16 (AUC = 0.83, 79.0%, AP = 0.83) than for AFP (AUC = 0.74, 61.7%, AP = 0.72). Combining miR-15a/16 with AFP increased the AUC to 0.86 (sensitivity 85.9%) and the AP to 0.85 and was significantly superior to the other markers in this study (P < 0.05 for all), as further demonstrated by the detection error tradeoff curves. Moreover, miR-15a/16 impressively showed potent diagnostic power in early-stage, small-tumor, and AFP-negative HCC. A validation cohort confirmed these results. Lastly, the simulated follow-up of patients further validated the diagnostic efficiency of miR-15a/16.ConclusionsWe developed and validated a plasma miR-15a/16-based machine learning model, which exhibited better diagnostic performance for the early diagnosis of HCC compared to that of AFP.

Dataset Information

Plasma and tumoral glypican-3 levels are correlated in patients with hepatitis C virus-related hepatocellular carcinoma.

Publications

Plasma and tumoral glypican-3 levels are correlated in patients with hepatitis C virus-related hepatocellular carcinoma.

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