TY - JOUR
T1 - A Biomarker Panel Based upon AFP, Fucosylated Kininogen and PEG-Precipitated IgG Is Highly Accurate for the Early Detection Hepatocellular Carcinoma in Patients with Cirrhosis in Phase II and Phase III Biomarker Evaluation
AU - Wang, Mengjun
AU - Singal, Amit G.
AU - Parikh, Neehar
AU - Kono, Yuko
AU - Marrero, Jorge
AU - Mehta, Anand
N1 - Publisher Copyright:
© 2022 by the authors.
PY - 2022/12
Y1 - 2022/12
N2 - We have previously identified alterations in glycosylation on serum proteins from patients with HCC and developed plate-based assays using lectins to detect the change in glycosylation. However, heterophilic antibodies, which increase with non-malignant liver disease, compromised these assays. To address this, we developed a method of polyethylene glycol (PEG) precipitation that removed the contaminating IgG and IgM but allowed for the lectin detection of the relevant glycoprotein. We found that this PEG-precipitated material itself could differentiate between cirrhosis and HCC. In the analysis of three training cohorts and one validation cohort, consisting of 571 patients, PEG-IgG had AUC values that ranged from 0.713 to 0.810. In the validation cohort, which contained samples from patients at a time of 1–6 months prior to HCC detection or 7+ months prior to detection, the AUC of this marker remained consistent (0.813 and 0.846, respectively). When this marker was incorporated into a biomarker algorithm that also consisted of AFP and fucosylated kininogen, the AUROC increased to 0.816–0.883 in the training cohort and was 0.909 in the external validation cohort. Biomarker performance was also examined though the analysis of partial ROC curves, at false positive values less than 10% (90-ROC), ≤20% (80-ROC) or ≤30% (70-ROC), which highlighted the algorithm’s improvement over the individual markers at clinically relevant specificity values.
AB - We have previously identified alterations in glycosylation on serum proteins from patients with HCC and developed plate-based assays using lectins to detect the change in glycosylation. However, heterophilic antibodies, which increase with non-malignant liver disease, compromised these assays. To address this, we developed a method of polyethylene glycol (PEG) precipitation that removed the contaminating IgG and IgM but allowed for the lectin detection of the relevant glycoprotein. We found that this PEG-precipitated material itself could differentiate between cirrhosis and HCC. In the analysis of three training cohorts and one validation cohort, consisting of 571 patients, PEG-IgG had AUC values that ranged from 0.713 to 0.810. In the validation cohort, which contained samples from patients at a time of 1–6 months prior to HCC detection or 7+ months prior to detection, the AUC of this marker remained consistent (0.813 and 0.846, respectively). When this marker was incorporated into a biomarker algorithm that also consisted of AFP and fucosylated kininogen, the AUROC increased to 0.816–0.883 in the training cohort and was 0.909 in the external validation cohort. Biomarker performance was also examined though the analysis of partial ROC curves, at false positive values less than 10% (90-ROC), ≤20% (80-ROC) or ≤30% (70-ROC), which highlighted the algorithm’s improvement over the individual markers at clinically relevant specificity values.
KW - biomarker
KW - glycosylation
KW - hepatocellular carcinoma
KW - human
KW - immunoglobulin
UR - http://www.scopus.com/inward/record.url?scp=85143603798&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85143603798&partnerID=8YFLogxK
U2 - 10.3390/cancers14235970
DO - 10.3390/cancers14235970
M3 - Article
C2 - 36497452
AN - SCOPUS:85143603798
SN - 2072-6694
VL - 14
JO - Cancers
JF - Cancers
IS - 23
M1 - 5970
ER -