Abstract
Background and aimsLiver transplantation (LT) can be offered to patients with Hepatocellular carcinoma (HCC) beyond Milan criteria. However, there are currently limited molecular markers on HCC explant histology to predict recurrence, which arises in up to 20% of LT recipients. The goal of our study was to derive a combined proteomic/transcriptomic signature on HCC explant predictive of recurrence post-transplant using unbiased, high-throughput approaches.MethodsPatients who received a LT for HCC beyond Milan criteria in the context of hepatitis B cirrhosis were identified. Tumor explants from patients with post-transplant HCC recurrence (N = 7) versus those without recurrence (N = 4) were analyzed by mass spectrometry and gene expression array. Univariate analysis was used to generate a combined proteomic/transcriptomic signature linked to recurrence. Significantly predictive genes and proteins were verified and internally validated by immunoblotting and immunohistochemistry.ResultsSeventy-nine proteins and 636 genes were significantly differentially expressed in HCC tumors with subsequent recurrence (p < 0.05). Univariate survival analysis identified Aldehyde Dehydrogenase 1 Family Member A1 (ALDH1A1) gene (HR = 0.084, 95%CI 0.01–0.68, p = 0.0152), ALDH1A1 protein (HR = 0.039, 95%CI 0.16–0.91, p = 0.03), Galectin 3 Binding Protein (LGALS3BP) gene (HR = 7.14, 95%CI 1.20–432.96, p = 0.03), LGALS3BP protein (HR = 2.6, 95%CI 1.1–6.1, p = 0.036), Galectin 3 (LGALS3) gene (HR = 2.89, 95%CI 1.01–8.3, p = 0.049) and LGALS3 protein (HR = 2.6, 95%CI 1.2–5.5, p = 0.015) as key dysregulated analytes in recurrent HCC. In concordance with our proteome findings, HCC recurrence was linked to decreased ALDH1A1 and increased LGALS3 protein expression by Western Blot. LGALS3BP protein expression was validated in 29 independent HCC samples.ConclusionsSignificantly increased LGALS3 and LGALS3BP gene and protein expression on explant were associated with post-transplant recurrence, whereas increased ALDH1A1 was associated with absence of recurrence in patients transplanted for HCC beyond Milan criteria. This combined proteomic/transcriptomic signature could help in predicting HCC recurrence risk and guide post-transplant surveillance.
Highlights
Hepatocellular carcinoma (HCC) is estimated to represent the fourth most common cause of cancer-related deaths globally [1]
Significantly increased LGALS3 and LGALS3BP gene and protein expression on explant were associated with post-transplant recurrence, whereas increased Aldehyde Dehydrogenase 1 Family Member A1 (ALDH1A1) was associated with absence of recurrence in patients transplanted for HCC beyond Milan criteria
This combined proteomic/transcriptomic signature could help in predict‐ ing HCC recurrence risk and guide post-transplant surveillance
Summary
Hepatocellular carcinoma (HCC) is estimated to represent the fourth most common cause of cancer-related deaths globally [1]. Selected patients with early-stage HCC are candidates for liver transplantation (LT) as a curative therapy. The safe expansion of selection criteria for LT in HCC hinges on an improved understanding of tumor biology through surrogate markers [1]. Such expanded criteria may allow extending the use of LT as a curative-intent treatment option to a greater number of patients, especially considering that HCC biology and progression are patient-dependent. Liver transplantation (LT) can be offered to patients with Hepatocellular carcinoma (HCC) beyond Milan criteria. There are currently limited molecular markers on HCC explant histology to predict recurrence, which arises in up to 20% of LT recipients. The goal of our study was to derive a combined proteomic/ transcriptomic signature on HCC explant predictive of recurrence post-transplant using unbiased, high-throughput approaches
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