Dataset Information

Heterogeneities of Site-Specific N-Glycosylation in HCC Tumors With Low and High AFP Concentrations.

ABSTRACT: Hepatocellular carcinoma (HCC) is still one of the malignant tumors with high morbidity and mortality in China and worldwide. Although alpha-fetoprotein (AFP) as well as core fucosylated AFP-L3 have been widely used as important biomarkers for HCC diagnosis and evaluation, the AFP level shows a huge variation among HCC patient populations. In addition, the AFP level has also been proved to be associated with pathological grade, progression, and survival of HCC patients. Understanding the intrinsic heterogeneities of HCC associated with AFP levels is essential for the molecular mechanism studies of HCC with different AFP levels as well as for the potential early diagnosis and personalized treatment of HCC with AFP negative. In this study, an integrated N-glycoproteomic and proteomic analysis of low and high AFP levels of HCC tumors was performed to investigate the intrinsic heterogeneities of site-specific glycosylation associated with different AFP levels of HCC. By large-scale profiling and quantifying more than 4,700 intact N-glycopeptides from 20 HCC and 20 paired paracancer samples, we identified many commonly altered site-specific N-glycans from HCC tumors regardless of AFP levels, including decreased modifications by oligo-mannose and sialylated bi-antennary glycans, and increased modifications by bisecting glycans. By relative quantifying the intact N-glycopeptides between low and high AFP tumor groups, the great heterogeneities of site-specific N-glycans between two groups of HCC tumors were also uncovered. We found that several sialylated but not core fucosylated tri-antennary glycans were uniquely increased in low AFP level of HCC tumors, while many core fucosylated bi-antennary or hybrid glycans as well as bisecting glycans were uniquely increased in high AFP tumors. The data provide a valuable resource for future HCC studies regarding the mechanism, heterogeneities and new biomarker discovery.

SUBMITTER: Zhao T

PROVIDER: S-EPMC7212448 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Publications

Heterogeneities of Site-Specific <i>N</i>-Glycosylation in HCC Tumors With Low and High AFP Concentrations.

Zhao Ting T Jia Li L Li Jun J Ma Chen C Wu Jingyu J Shen Jiechen J Dang Liuyi L Zhu Bojing B Li Pengfei P Zhi Yuan Y Lan Rongxia R Xu Yintai Y Hao Zhifang Z Chai Yichao Y Li Qingshan Q Hu Liangshuo L Sun Shisheng S

Frontiers in oncology 20200421

Hepatocellular carcinoma (HCC) is still one of the malignant tumors with high morbidity and mortality in China and worldwide. Although alpha-fetoprotein (AFP) as well as core fucosylated AFP-L3 have been widely used as important biomarkers for HCC diagnosis and evaluation, the AFP level shows a huge variation among HCC patient populations. In addition, the AFP level has also been proved to be associated with pathological grade, progression, and survival of HCC patients. Understanding the intrins ...[more]

PMID: 32426269

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Project description:BackgroundThe methylation SEPT9 (mSEPT9) appeared to be effective for hepatocellular carcinoma (HCC) detection. However, its performance in high-risk population has not been validated. We designed a pilot study and aimed to investigate the performance of mSEPT9, AFP, PIVKA-II and their combination in hepatic cirrhosis (HC) population.MethodsA training cohort was established including 103 HCC and 114 HC patients. 10 ml blood was collected from each patient with K2EDTA tubes, and 3-4 ml plasma was extracted for subsequent tests. The performance of mSEPT9, AFP, PIVKA-II and their combination was optimized by the training cohort. Test performance was prospectively validated with a validation cohort, including 51 HCC and 121 HC patients.ResultsAt the optimal thresholds in the training cohort, the sensitivity, specificity and area under curve (AUC) was 72.82%, 89.47%, 0.84, and 48.57%, 89.92%, 0.79, and 63.64%, 95.95%, 0.79 for mSEPT9, AFP and PIVKA-II, respectively. The combined test significantly increased the sensitivity to 84.47% (P < 0.05) at the specificity of 86.84% with an AUC of 0.91. Stage-dependent performance was observed with all single markers and their combination in plasma marker levels, positive detection rate (PDR) and AUC. Moderate correlation was found between mSEPT9 and AFP plasma levels (r = 0.527, P < 0.0001). Good complementarity was found between any two of the three markers, providing optimal sensitivity in HCC detection when used in combination. Subsequent validation achieved a sensitivity, specificity and AUC of 65.31%, 92.86%, 0.80, and 44.24%, 89.26%, 0.75, and 62.22%, 95.27%, 0.78 for mSEPT9, AFP and PIVKA-II, respectively. The combined test yielded a significantly increased sensitivity of 84.00% (P < 0.05) at 85.57% specificity, with an AUC at 0.89.ConclusionsThe performance was optimal by the combination of mSEPT9, AFP, PIVKA-II compared with any single marker, and the combination may be effective for HCC opportunistic screening in HC population.

Project description:BackgroundSerum sphingolipids are widely involved in the development of hepatocellular carcinoma (HCC). We investigated the serum sphingolipid profile in patients with HCC or cirrhosis and explored the potential diagnostic efficiency of serum sphingolipid metabolites which may be helpful in differentiating HCC including α-fetoprotein (AFP)-negative HCC from cirrhosis.MethodsSeventy-two HCC patients (including 24 AFP-negative HCC) and 104 cirrhotic patients were consecutively enrolled in this study. High-performance liquid chromatography-tandem mass spectrometry was used to detect a panel of 57 serum sphingolipid metabolites.ResultsTwenty-four sphingolipid metabolites showed significant differences between HCC and cirrhotic patients (all P < 0.05). Sphingosine (d18:1)-1-P was found to have the potential to differentiate HCC from cirrhosis by orthogonal partial least squares discriminant analysis (OPLS-DA). There was no significant difference in the efficacy of Sphingosine (d18:1)-1-P and AFP to distinguish HCC from cirrhosis, and the area under the receiver operating curve (AUC) were 0.85 and 0.83 (P > 0.05), respectively. When the cut-off value of Sphingosine (d18:1)-1-P was set at 56.29 pmol/0.1 ml, the sensitivity and specificity were 79.20% and 78.70%, respectively. Notably, the upregulation of Sphingosine (d18:1)-1-P could also distinguish AFP-negative HCC from cirrhosis with an AUC of 0.79. The sensitivity and specificity were 62.50% and 77.90% at a cut-off value of 56.29 pmol/0.1 ml. Spearman rank correlation analysis revealed that serum Sphingosine (d18:1)-1-P was not correlated with AFP in patients with cirrhosis, AFP-positive HCC, and AFP-negative HCC. Moreover, the difference in the diagnostic efficiency of serum Sphingosine (d18:1)-1-P was not statistically significant between tumor size (≤2 cm vs. >2 cm, P = 0.476). Also, there was no difference among patients with different TNM stages and BCLC stages.ConclusionThe upregulation of serum Sphingosine (d18:1)-1-P exhibits good diagnostic performance for HCC. Particularly, Sphingosine (d18:1)-1-P could also serve as a biomarker for the diagnosis of AFP-negative HCC. These findings may contribute to the non-invasive diagnosis of HCC including AFP-negative HCC.

Dataset Information

Heterogeneities of Site-Specific N-Glycosylation in HCC Tumors With Low and High AFP Concentrations.

Publications

Heterogeneities of Site-Specific <i>N</i>-Glycosylation in HCC Tumors With Low and High AFP Concentrations.

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