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Detection of hepatocellular carcinoma using glycomic analysis.

ABSTRACT: PURPOSE:Hepatocellular carcinoma (HCC) represents an increasing health problem in the United States. Serum alpha-fetoprotein, the currently used clinical marker, is elevated in only approximately 60% of HCC patients; therefore, the identification of additional markers is expected to have significant public health impact. The objective of our study was to quantitatively assess N-glycans originating from serum glycoproteins as alternative markers for the detection of HCC. EXPERIMENTAL DESIGN:We used matrix-assisted laser desorption/ionization time-of-flight mass spectrometry for quantitative comparison of 83 N-glycans in serum samples of 202 participants (73 HCC cases, 77 age- and gender-matched cancer-free controls, and 52 patients with chronic liver disease). N-glycans were enzymatically released from serum glycoproteins and permethylated before mass spectrometric quantification. RESULTS:The abundance of 57 N-glycans was significantly altered in HCC patients compared with controls. The sensitivity of six individual glycans evaluated for separation of HCC cases from population controls ranged from 73% to 90%, and the specificity ranged from 36% to 91%. A combination of three selected N-glycans was sufficient to classify HCC with 90% sensitivity and 89% specificity in an independent validation set of patients with chronic liver disease. The three N-glycans remained associated with HCC after adjustment for chronic viral infection and other known covariates, whereas the other glycans increased significantly at earlier stages of the progression of chronic viral infection to HCC. CONCLUSION:A set of three identified N-glycans is sufficient for the detection of HCC with 90% prediction accuracy in a population with high rates of hepatitis C viral infection. Further evaluation of a wider clinical utility of these candidate markers is warranted.

SUBMITTER: Goldman R

PROVIDER: S-EPMC2850198 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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Detection of hepatocellular carcinoma using glycomic analysis.

Goldman Radoslav R Ressom Habtom W HW Varghese Rency S RS Goldman Lenka L Bascug Gregory G Loffredo Christopher A CA Abdel-Hamid Mohamed M Gouda Iman I Ezzat Sameera S Kyselova Zuzana Z Mechref Yehia Y Novotny Milos V MV

Clinical cancer research : an official journal of the American Association for Cancer Research 20090217 5

<h4>Purpose</h4>Hepatocellular carcinoma (HCC) represents an increasing health problem in the United States. Serum alpha-fetoprotein, the currently used clinical marker, is elevated in only approximately 60% of HCC patients; therefore, the identification of additional markers is expected to have significant public health impact. The objective of our study was to quantitatively assess N-glycans originating from serum glycoproteins as alternative markers for the detection of HCC.<h4>Experimental d ...[more]

PMID: 19223512

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Project description:Tumor‑associated (TA) autoantibodies are considered to be promising biomarkers for the early detection of cancer, prior to the development of clinical symptoms. In the present study, a novel TA autoantibody was detected, which may prove to be useful as a diagnostic marker of human HCC using an HBx‑transgenic (HBx‑tg) hepatocellular carcinoma (HCC) mouse model. Its target antigen was identified as the bromodomain‑containing protein 2 (BRD2), a transcriptional regulator that plays a pivotal role in the transcriptional control of diverse genes. BRD2 was upregulated in HCC tissues of the H‑ras12V‑tg mouse and human subjects, as demonstrated using western blotting or immunohistochemical analysis, with the BRD2 autoantibody. In addition, the truncated BRD2 reactive to the BRD2 autoantibody was detected in tumor cell‑derived exosomes, which possibly activated TA immune responses and the generation of autoantibodies. For the detection of the serum BRD2 autoantibody, epitope mimicries of autoantigenic BRD2 were screened from a random cyclic peptide CX7C library with the BRD2 autoantibody. A mimotope with the sequence of CTSVFLPHC, which was cyclized by one pair of cysteine residues, exhibited high affinity to the BRD2 autoantibody and competitively inhibited the binding of the autoantibody to the cellular BRD2 antigen. The use of this cyclic peptide as a capture antigen in human serum enzyme‑linked immunosorbent assay allowed the distinction of patients with HCC from healthy subjects with 64.41% sensitivity and 82.42% specificity (area under the ROC curve, 0.7761), which is superior to serum alpha‑fetoprotein (AFP; 35.83% sensitivity; 100% specificity; area under the ROC curve, 0.5337) for the diagnosis of HCC. In addition, the detection of the BRD2 autoantibody combined with other autoantibody biomarkers or AFP has increased the accuracy of HCC diagnosis, suggesting that the combinational detection of cancer biomarkers, including the BRD2 autoantibody, is a promising assay for HCC diagnosis.

Dataset Information

Detection of hepatocellular carcinoma using glycomic analysis.

Publications

Detection of hepatocellular carcinoma using glycomic analysis.

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