Abstract
Chronic Hepatitis B (HB) is the main risk factor for chronic liver disease (CLD) and hepatocellular carcinoma (HCC) in many low-resource countries, where diagnosis is constrained by lack of clinical, histopathological and biomarker resources. We have used proteomics to detect plasma biomarkers that outperform α-Fetoprotein (AFP), the most widely used biomarker for HCC diagnosis in low-resource contexts. Deep-plasma proteome analysis was performed in HCC patients, patients with CLD and in HB-carrier controls from Thailand (South-East Asia) and The Gambia (West-Africa). Mass spectrometry profiling identified latent-transforming growth factor β binding-protein 2 (LTBP2) and Osteopontin (OPN) as being significantly elevated in HCC versus CLD and controls. These two proteins were further analyzed by ELISA in a total of 684 plasma samples, including 183 HCC, 274 CLD and 227 asymptomatic controls. When combined, LTBP2 and OPN showed an area under the receiver operating curve of 0.85 in distinguishing HCC from CLD in subjects with AFP <20 ng/mL. In a prospective cohort of 115 CLD patients from Korea, increased plasma levels of LTBP2 and/or OPN were detected in plasma collected over 2 years prior to diagnosis in 21 subjects who developed HCC. Thus, the combination of LTBP2 and OPN outperformed AFP for diagnosis and prediction of HCC and may therefore improve biomarker-based detection of HBV-related HCC.
Highlights
Hepatocellular carcinoma (HCC) represents over 80% of primary liver cancer (PLC) cases and is the 3rd most frequent cause of cancer-related death worldwide, with considerable geographic variation in rates and aetiology 1. These variations are due to differences in the distribution of risk factors such as chronic infections with hepatitis B (HBV) virus or hepatitis C (HCV) virus, dietary exposure to the mycotoxin aflatoxin B1 (AFB1), alcohol consumption and metabolic syndromes associated with overweight/obesity
We have identified another potential biomarker, LatentTransforming Growth Factor β Binding-Protein 2 (LTBP2). This biomarker was identified by mass spectrometry with high confidence, characterized by high peptide and protein probabilities (≥99% and ≥97%, respectively) with sequence coverage of 54% in plasma samples of chronic liver disease (CLD) and HCC patients
Case-control 1 (TLCS, Thailand) and 2 (GLDS, The Gambia), have recruited patients with mostly advanced forms of HCC, whereas the CLD group was constituted of patients with chronic active hepatitis B (CHB)
Summary
Hepatocellular carcinoma (HCC) represents over 80% of primary liver cancer (PLC) cases and is the 3rd most frequent cause of cancer-related death worldwide, with considerable geographic variation in rates and aetiology 1. In the Asia-Pacific region and in west Africa, PLC ranks as the most frequent cancer in males and the 3rd in females, with age standardized incidence rates (ASR, World standard) of 53 in males and 20 in females in The Gambia, and of 41 in males and 20 in females in Thailand 2, 3 In both countries, the main attributable risk factor is HBV, with significant differences in HBV genotypes (B and/or C, in Thailand, E in The Gambia) and in levels of exposure to AFB1, which is considered as a minor, non-negligible, risk factor in Thailand but represents a major contaminant of staple diets in The Gambia 4, 5. In Thailand, cholangiocarcinoma (CC), the second most common form of PLC, represents about 30% of the cases and up to 75% in the northern and eastern parts of the country 6
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