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
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 ad...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-12-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/14/23/5970 |
| _version_ | 1797463508711899136 |
|---|---|
| author | Mengjun Wang Amit G. Singal Neehar Parikh Yuko Kono Jorge Marrero Anand Mehta |
| author_facet | Mengjun Wang Amit G. Singal Neehar Parikh Yuko Kono Jorge Marrero Anand Mehta |
| author_sort | Mengjun Wang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T17:51:43Z |
| format | Article |
| id | doaj.art-ccddacd7fbd74032a3174b8f8f55d89c |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T17:51:43Z |
| publishDate | 2022-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-ccddacd7fbd74032a3174b8f8f55d89c2023-11-24T10:41:40ZengMDPI AGCancers2072-66942022-12-011423597010.3390/cancers14235970A 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 EvaluationMengjun Wang0Amit G. Singal1Neehar Parikh2Yuko Kono3Jorge Marrero4Anand Mehta5Basic Science Building Room 310, Department of Cell and Molecular Pharmacology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USADivision of Digestive and Liver Diseases, University of Texas Southwestern, 5959 Harry Hines Blvd POB I Suite 420B, Dallas, TX 75201, USADepartment of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USADivision of Gastroenterology, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USADivision of Gastroenterology, University of Pennsylvania, 3400 Civic Center Boulevard South Pavilion, 4th Floor, Philadelphia, PA 19104, USABasic Science Building Room 310, Department of Cell and Molecular Pharmacology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USAWe 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.https://www.mdpi.com/2072-6694/14/23/5970biomarkerhepatocellular carcinomaglycosylationimmunoglobulinhuman |
| spellingShingle | Mengjun Wang Amit G. Singal Neehar Parikh Yuko Kono Jorge Marrero Anand Mehta 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 Cancers biomarker hepatocellular carcinoma glycosylation immunoglobulin human |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | biomarker hepatocellular carcinoma glycosylation immunoglobulin human |
| url | https://www.mdpi.com/2072-6694/14/23/5970 |
| work_keys_str_mv | AT mengjunwang abiomarkerpanelbaseduponafpfucosylatedkininogenandpegprecipitatediggishighlyaccuratefortheearlydetectionhepatocellularcarcinomainpatientswithcirrhosisinphaseiiandphaseiiibiomarkerevaluation AT amitgsingal abiomarkerpanelbaseduponafpfucosylatedkininogenandpegprecipitatediggishighlyaccuratefortheearlydetectionhepatocellularcarcinomainpatientswithcirrhosisinphaseiiandphaseiiibiomarkerevaluation AT neeharparikh abiomarkerpanelbaseduponafpfucosylatedkininogenandpegprecipitatediggishighlyaccuratefortheearlydetectionhepatocellularcarcinomainpatientswithcirrhosisinphaseiiandphaseiiibiomarkerevaluation AT yukokono abiomarkerpanelbaseduponafpfucosylatedkininogenandpegprecipitatediggishighlyaccuratefortheearlydetectionhepatocellularcarcinomainpatientswithcirrhosisinphaseiiandphaseiiibiomarkerevaluation AT jorgemarrero abiomarkerpanelbaseduponafpfucosylatedkininogenandpegprecipitatediggishighlyaccuratefortheearlydetectionhepatocellularcarcinomainpatientswithcirrhosisinphaseiiandphaseiiibiomarkerevaluation AT anandmehta abiomarkerpanelbaseduponafpfucosylatedkininogenandpegprecipitatediggishighlyaccuratefortheearlydetectionhepatocellularcarcinomainpatientswithcirrhosisinphaseiiandphaseiiibiomarkerevaluation AT mengjunwang biomarkerpanelbaseduponafpfucosylatedkininogenandpegprecipitatediggishighlyaccuratefortheearlydetectionhepatocellularcarcinomainpatientswithcirrhosisinphaseiiandphaseiiibiomarkerevaluation AT amitgsingal biomarkerpanelbaseduponafpfucosylatedkininogenandpegprecipitatediggishighlyaccuratefortheearlydetectionhepatocellularcarcinomainpatientswithcirrhosisinphaseiiandphaseiiibiomarkerevaluation AT neeharparikh biomarkerpanelbaseduponafpfucosylatedkininogenandpegprecipitatediggishighlyaccuratefortheearlydetectionhepatocellularcarcinomainpatientswithcirrhosisinphaseiiandphaseiiibiomarkerevaluation AT yukokono biomarkerpanelbaseduponafpfucosylatedkininogenandpegprecipitatediggishighlyaccuratefortheearlydetectionhepatocellularcarcinomainpatientswithcirrhosisinphaseiiandphaseiiibiomarkerevaluation AT jorgemarrero biomarkerpanelbaseduponafpfucosylatedkininogenandpegprecipitatediggishighlyaccuratefortheearlydetectionhepatocellularcarcinomainpatientswithcirrhosisinphaseiiandphaseiiibiomarkerevaluation AT anandmehta biomarkerpanelbaseduponafpfucosylatedkininogenandpegprecipitatediggishighlyaccuratefortheearlydetectionhepatocellularcarcinomainpatientswithcirrhosisinphaseiiandphaseiiibiomarkerevaluation |