Plasma proteome atlas for differentiating tumor stage and post-surgical prognosis of hepatocellular carcinoma and cholangiocarcinoma

Abstract

Although mass spectrometry-based plasma proteomics enables sensitive and large-scale discovery and validation of biomarkers for various diseases, its integrative application to hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) is not well investigated. Therefore, we analyzed albumin-and immunoglobulin G-depleted plasma samples from 148 and 60 patients with HCC and CCA, respectively, using liquid chromatography-tandem mass spectrometry. The algorithm used to measure the content of each protein was the percentage of exponentially modified protein abundance index. From 5320 proteins assayed in plasma, 53 and 25 biomarker candidates were identified for HCC and CCA, respectively. The abundance of six and two HCC markers particularly protruded in stage II and III, respectively, whereas plasma serine protease inhibitor was the sole marker the level of which steadily decreased with CCA progression. From a prognostic facet, we showed candidate markers and their cutoff levels for evaluating probability of tumor recurrence and patient survival period. Combination Kaplan-Meier models showed that HCC stage III or IV and both the content of alpha-2-HS-glycoprotein and apolipoprotein CIII <0.2% exhibited the poorest post-surgical recurrence-free and overall survivals. Furthermore, the content of afamin �0.2% played a significant role on the poor prognosis in patients with CCA. Our findings, taken together, characterized novel plasma biomarker signatures in dissecting tumor stages and post-surgical outcomes of HCC and CCA.

Biliary Strictures and Cholangiocarcinoma – Untangling a Diagnostic Conundrum

“…Interestingly, the authors reported that levels of plasma serine protease inhibitor inversely correlated with tumour development (stage I to IV). In addition, levels of afamain - a human plasma vitamin E-binding glycoprotein, and previously described ovarian cancer tumour marker ( 157 ), were associated with poor prognosis in CCA ( 156 ). Despite their potential, these similarly require further validation in larger and randomized cohorts.…”

“…Other serum proteins have been reported as stage specific and prognostic in CCA. A recent study analysed the serum proteome of 148 HCC and 60 CCA patients by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and found 25 differently expressed proteins in CCA patients, with AUC ranging from 0.701 to 0.823 ( 156 ). Interestingly, the authors reported that levels of plasma serine protease inhibitor inversely correlated with tumour development (stage I to IV).…”

Proteomic Profiling and Artificial Intelligence for Hepatocellular Carcinoma Translational Medicine

“…Liquid biopsies in combination with LC-MS/MS-based proteomics arise as a powerful high-sensitive and non-invasive platform for the identification of biomarkers at extremely low concentrations in a complex mixture [ 35 ]. Unlike conventional tissue biopsy, liquid biopsy is a non-invasive approach, which allows repeated analysis to enable monitoring tumor progression, metastasis, and recurrence, as well as treatment response.…”

“…Among them, aldo-keto reductase family 1 member B10 (AKR1B10) and cathepsin A (CTSA) in combination with AFP showed the greatest area under the curve (AUC). Additionally, MS-based plasma proteomic atlas containing 53 and 25 molecular biomarkers for HCC and cholangiocarcinoma, respectively, has been constructed to differentiate tumor stage and to assess post-operative prognosis [ 35 ]. Six and two HCC biomarkers were abundant in phase II and phase III HCC, respectively, including alpha-2-HS-glycoprotein and apolipoprotein CIII (both ≥0.2%), Ig λ-chain VI region NEWM (≥1.0%), and serum amyloid P component (≥0.3%), which positively correlated with the best OS and RFS.…”

Biomarker Candidates for Tumors Identified from Deep-Profiled Plasma Stem Predominantly from the Low Abundant Area

“…Enroth et al found plasma protein biomarker signatures for ovarian cancer 22 , but performed no validation. He et al showed that for hepatocellular carcinoma and cholangiocarcinoma, biomarker candidates could be identified from plasma; validation of these candidates is still pending 23 . Zhou et at.…”