Source Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.

This study was to identify a biomarker that could improve α-fetoprotein (AFP) performance in hepatocellular carcinoma (HCC) surveillance among patients with cirrhosis. We performed proteomic profiling of plasma from patients with cirrhosis or HCC and validated selected candidate HCC biomarkers in two geographically distinct cohorts in order to include HCC of different etiologies. Mass spectrometry profiling of highly fractionated plasma from 18 cirrhosis and 17 HCC patients identified osteopontin (OPN) as significantly upregulated in HCC cases compared to cirrhosis controls. OPN levels were subsequently measured in 312 plasma samples collected from 131 HCC patients, 76 cirrhosis patients, 52 chronic hepatitis C (CHC) and B (CHB) patients and 53 healthy controls, in two independent cohorts. OPN plasma levels were significantly elevated in HCC patients compared to cirrhosis, CHC, CHB or healthy controls, in both cohorts. OPN alone or in combination with AFP had significantly better area under the receiver operating characteristic curve compared to AFP in comparing cirrhosis and HCC in both cohorts. OPN overall performance remained higher than AFP in comparing cirrhosis and the following HCC groups: HCV-related HCC, HBV-associated HCC and early HCC. OPN had also a good sensitivity in AFP negative HCC. In a pilot prospective study including 22 patients who developed HCC during follow-up, OPN was already elevated a year prior to diagnosis. Conclusion: OPN was more sensitive than AFP for the diagnosis of HCC in all studied HCC groups. In addition, OPN performance remained intact in samples collected a year prior to diagnosis.