Plasma MicroRNA Panel Predicts Early Tumor Recurrence in Patients with Hepatocellular Carcinoma after Liver Transplantation

Abstract

Background: This study aimed to evaluate the role of plasma microRNA panel (miR-122, miR-192, miR-21, miR-223, miR-26a, miR-27a and miR-801) for prediction and surveillance of early tumor recurrence in hepatocellular carcinoma (HCC) patients who had undergone liver transplantation (LT). Methods: The expression of plasma microRNA panel was assayed in 193 HCC patients (training cohort, n =151; validation cohort, n = 42). Sensitivity and specificity for detecting post-transplant HCC recurrence, and the relationship of microRNA panel expression with clinical characteristics were analyzed accordingly. The prognostic value of microRNA panel was compared with that of AFP (alpha-fetoprotein) and DCP (Des-gamma-carboxyprothrombin). Cox regression analyses were used to evaluate independent prognostic factors. Results: In the training cohort, the rate of positive plasma microRNA panel status at 7-14 days after LT (late phase; 44.2%) decreased than that before (76.2%, P < 0.001) and 1-6 days after LT (early phase; 78.5%, P < 0.001). At late phase, positive microRNA panel status correlated with higher early tumor recurrence rate (one year after LT) than negative status (45.9% vs 10.7%; P < 0.001). Patients with persistent positive microRNA panel status both before and after LT had the highest early tumor recurrence rate in this cohort (54.9%, P < 0.001). The results were consistent in the validation cohort. Cox regression analysis found that positive plasma microRNA panel status at late phase was the only independent risk factor for early recurrence (HR: 4.903, 95% CI = 2.195 - 10.951; P < 0.001). Dynamic monitoring demonstrated plasma microRNA panel status changed from negative to positive earlier than AFP and DCP upon recurrence, and the median time between positivity of plasma microRNA and imaging evidence of recurrence was 2.4 (0.5-10.0) months. Conclusions: Plasma microRNA panel could be a noninvasive biomarker for prediction and surveillance of early tumor recurrence in HCC patients who have undergone LT.

Is liquid biopsy the future commutator of decision-making in liver transplantation for hepatocellular carcinoma?

“…(III) Also, as for any other biomarkers, a perfect performance cannot be expected. Some of the selected patients may nevertheless develop recurrence, but sequential blood testing will help detecting early relapse; this is supported by studies demonstrating the prognostic value of post-LT blood samples analyzes ( 22 , 36 , 37 , 56 ). (IV) Finally, there has been increasing data demonstrating the value of downstaging strategies to optimize patients’ selection and reduce the risk of recurrence after LT ( 65 ).…”

“…Regarding albumin, it would be worth assessing whether its mutation may impact the level of circulating mRNA, as albumin is a frequently mutated gene in HCC ( 61 , 62 ). The data on circulating miRNAs were surprisingly scarce but provided interesting findings, either highlighting the value of a particular biomarker such as miR-1246 ( 37 ) or of a specific panel ( 36 ). Exosomes deserve to be more extensively explored, particularly for exosomal mRNA, which may be highly contributive.…”

“…Despite its attractive characteristics, circulating miRNAs was rarely investigated in LT, with a total of four studies: two focusing on LT ( 36 , 37 ) ( Table 2 ) and two studies also including other treatments ( 42 , 43 ).…”

“…Huang et al. designed a panel of seven circulating miRNAs (miR-122, miR-192, miR-21, miR-223, miR-26a, miR-27a, and miR-801), which was tested preoperatively, 1–6 days (early phase) and 7–14 days (late phase) after LT ( 36 ). As first finding, positive miRNA panel status at late phase was the only independent prognostic factor of recurrence (HR, 4.90; 95% CI, 2.20–10.95; p < 0.001).…”

European Society for Organ Transplantation Consensus Statement on Biomarkers in Liver Transplantation

“…Micro RNAs are short, non-coding RNAs that post-transcriptionally regulate gene expression by binding with mRNA; circulating levels of both have been measured in HCC LT recipients in the context of two and five studies, respectively. The preliminary results they report suggest potential associations between HCC recurrence and circulating pre-LT mRNAs encoding different proteins (albumin, h-TERT, AFP) as well as between HCC recurrence and circulating post-LT miRNAs [ 49 – 51 , 54 , 55 ]. Exosomal RNAs and circulating free DNA have also been evaluated in preliminary clinical studies and variably associated with post-LT recurrence and survival [ 47 , 48 ].…”