Yolk sac tumor but not seminoma or teratoma is associated with abnormal epigenetic reprogramming pathway and shows frequent hypermethylation of various tumor suppressor genes

Abstract

Germ cell tumors (GCTs) are thought to arise from primordial germ cells (PGCs) that undergo epigenetic reprogramming: erasure of the somatic imprint in the genital ridge, and re-establishment of the sex-specific imprint at gametogenesis in the developing gonad. Previous studies suggested that GCTs show epigenetic patterns reflecting the reprogramming process of PGCs; however, epigenetic alterations of imprinted genes and their relationship with the methylation status of tumor suppressor genes (TSGs) have not been comprehensively studied. We analyzed the methylation status of the H19 and SNRPN differential methylated regions (DMRs) and the promoter region of 17 TSGs, and the expression status of H19, IGF2 and SNRPN in 45 GCTs, and found that 25 and 20 were in the normal and abnormal reprogramming pathways, respectively, defined on the basis of the methylation status of the two DMRs and the anatomical tumor site. The methylation pattern of the H19 and SNRPN DMRs was total erasure in seminomas, mostly physiological in teratomas, and various in yolk sac tumors. There were no correlations between the methylation status of the H19 DMR and mono- or biallelic expression of H19 or IGF2. Furthermore, we found that yolk sac tumors had a higher number of methylated TSGs than seminomas (P < 0.001) teratomas (P = 0.004) or other childhood tumors. While TSG methylation was known to have prognostic implications in various cancers, it did not affect the outcomes of patients with yolk sac tumor, suggesting that mechanisms of TSG methylation may be different between yolk sac tumor and other cancers.