Promotor methylation status of <scp>MAPK4</scp> is a novel epigenetic biomarker for prognosis of recurrence in patients with thymic epithelial tumors

The prognosis of thymic epithelial tumors (TETs) currently relies on the commonly adopted WHO classification and Masaoka staging system, which cannot reflect the undefined biological behaviors limiting them as prognostic factors.In this study, we first identified 40 genes and 179 genes, respectively that were epigenetically upregulated and silenced, corresponding to a total of 509 functionally methylated CpG sites between thymomas and thymic carcinomas by using the TCGA dataset.The methylation β-values of cg20068620 in MAPK4 and cg18770944 in USP51 were significantly associated with recurrence-free survival (RFS). In the independent validation cohort, only WHO classification and methylation β-values of cg20068620 in MAPK4 were independent prognostic factors for RFS in Chinese patients with TETs. A linear weighted model including these two factors was used to calculate the recurrence risk score (RRS). Time-dependent ROC curve analysis revealed that RRS was overwhelmingly superior to WHO classification for predicting 3-, 5-, and 10-year RFS and Masaoka stage for 3- and 5-year RFS.These results suggested that the methylation site cg20068620 in MAPK4 can improve the accuracy of the WHO classification alone regarding the prognostic value of TETs recurrence.