Changes in the Glycosylation of Kininogen and the Development of a Kininogen-Based Algorithm for the Early Detection of HCC

Abstract

Background Hepatocellular carcinoma (HCC) has the greatest increase in mortality among all solids tumors in the United States related to low rates of early tumor detection. Development of non-invasive biomarkers for early detection of HCC may reduce HCC-related mortality. Methods We have developed an algorithm that combines routinely observed clinical values into a single equation that in a study of > 3,000 patients from 5 independent sites, improved detection of HCC as compared to the currently used biomarker, alpha-feto-protein (AFP), by 4–20%. However, this algorithm had limited benefit in those with AFP <20 ng/mL. To that end, we have developed a secondary algorithm that incorporates a marker, fucosylated kininogen, to improve the detection of HCC, especially in those with AFP <20 ng/mL and early stage disease. Results The ability to detect early stage AFP negative (AFP< 20 ng/mL) HCC increased from 0% (AFP alone) to 89% (for the new algorithm). Glycan analysis revealed that kininogen has several glycan modifications that have been associated with HCC, but often not with specific proteins, including increased levels of core and outer-arm fucosylation and increased branching. Conclusions An algorithm combining fucosylated kininogen, alpha fetoprotein, and clinical characteristics is highly accurate for early HCC detection. Impact Our biomarker algorithm could significantly improve early HCC detection and curative treatment eligibility in patients with cirrhosis.

Epidemiology and surveillance for hepatocellular carcinoma: New trends

“…86 Another panel including AFP, fucosylated kininogen, age, gender, alkaline phosphatase, and alanine aminotransferase demonstrated a c-statistic of 0.97 (95% CI 0.95-0.99) for early HCC detection in a small phase II biomarker study of 162 patients (69 early HCC, 93 cirrhosis). 87 Finally, a methylated DNA marker panel had a c-statistic of 0.96 (95% CI 0.93-0.99), with a sensitivity exceeding 90%, for early HCC detection in a phase II study with 146 patients (95 HCC and 51 cirrhosis). 88 Similar to individual biomarker studies, these data are promising but still require validation in large phase III biomarker studies.…”

New Blood Biomarkers for the Diagnosis of AFP-Negative Hepatocellular Carcinoma

“…Incorporation of some new biomarkers into a diagnostic model may be valuable to improve the diagnostic performance of the model. Wang et al (175) found that fucosylation was elevated in HCC patients compared with cirrhotic patients and developed a diagnostic model that incorporated fucosylated kininogen with age, gender, serum alkaline phosphatase, alanine aminotransaminase levels, and AFP for predicting HCC incidence. This model has an AUROC of 0.970 and a true positive rate of 89% for detecting ANHC and early-stage HCC patients, whereas the AUROC of AFP was 0.597 with a true positive rate of 0% at a 5% false positive rate and presented better diagnostic performance compared with their previous model based on simple clinical metrics.…”

Glycoproteomic markers of hepatocellular carcinoma‐mass spectrometry based approaches

“…Further research on these markers is needed where some, such as hemopexin, have been demonstrated to confer only marginally better results than AFP (Kobayashi et al, ). More recently, fucosylated kininogen has been shown to have great potential as a marker in combination with other clinical variables (Wang et al, ). Only GP73 has undergone a multi‐center epidemiological study to determine real‐world sensitivity and specificity values (Mao et al, ).…”

“…LC‐ESI analysis has been used to profile glycans for a number of cancers, including ovarian (Leiserowitz et al, ; Kim et al, ), pancreatic (Zhao et al, ), HCC (Chandler et al, ; Tsai et al, ; Wang et al, ), and prostate cancer (Hua et al, ), among others. There have been a number of studies on global screening of glycans from serum for HCC biomarker studies.…”