DNA methylation of SOCS1/2/3 predicts hepatocellular carcinoma recurrence after liver transplantation.

Abstract

DNA methylation status of SOCS1/SOCS2/SOCS3 is intensely involved in the development and progression of hepatocellular carcinoma (HCC). This study explored its prognostic value for HCC recurrence after liver transplantation (LT). Clinical data from 62 HCC patients who underwent LT at our centre were retrospectively collected. The SOCS1/2/3 methylation level were determined using next generation sequencing. Overall, 244 methylated sites at the SOCS1/2/3 promoter were identified. Multivariate analysis yielded the methylated sites SOCS2-1-90 (Chromosome 12, Position 93963982; HR 0.386, 95% CI 0.149-0.998) and SOCS1-1-68 (Chromosome 16, Position 11350699; HR 4.376, 95% CI 1.324-14.459) as independent predictors of post-LT HCC recurrence. Patients were divided into highly- and lowly methylated groups according to the median SOCS1-1-68 (0.95%) and SOCS2-1-90 (1.05%) methylation levels. Highly methylated SOCS2-1-90 was associated with significantly lower AFP levels (P = 0.008), decreased proportion of maximal tumour size > 8cm (P = 0.02), and better pathological grading (P = 0.06). Conversely, patients in the highly methylated SOCS1-1-68 group had higher AFP levels (P = 0.043). Kaplan-Meier analyses revealed that patients with highly methylated SOCS2-1-90 had increased recurrence free survival (RFS) and overall survival (OS) rates when compared with those with lowly methylated SOCS2-1-90 (P = 0.0041 and 0.012, respectively). Nevertheless, the correlation between methylated SOCS1-1-68 and cumulative recurrence rates was less pronounced (P = 0.098). Subgroup analyses demonstrated that patients meeting the Milan criteria, UCSF criteria, Metroticket 2.0 Model or Hangzhou criteria with highly methylated SOCS2-1-90 had the best RFS rates. DNA methylation of SOCS2-1-90 is a novel biomarker for predicting post-transplant HCC recurrence.