Abstract
BackgroundHuman male germ cell tumors (GCTs) arise from undifferentiated primordial germ cells (PGCs), a stage in which extensive methylation reprogramming occurs. GCTs exhibit pluripotentality and are highly sensitive to cisplatin therapy. The molecular basis of germ cell (GC) transformation, differentiation, and exquisite treatment response is poorly understood.ResultsTo assess the role and mechanism of promoter hypermethylation, we analyzed CpG islands of 21 gene promoters by methylation-specific PCR in seminomatous (SGCT) and nonseminomatous (NSGCT) GCTs. We found 60% of the NSGCTs demonstrating methylation in one or more gene promoters whereas SGCTs showed a near-absence of methylation, therefore identifying distinct methylation patterns in the two major histologies of GCT. DNA repair genes MGMT, RASSF1A, and BRCA1, and a transcriptional repressor gene HIC1, were frequently methylated in the NSGCTs. The promoter hypermethylation was associated with gene silencing in most methylated genes, and reactivation of gene expression occured upon treatment with 5-Aza-2' deoxycytidine in GCT cell lines.ConclusionsOur results, therefore, suggest a potential role for epigenetic modification of critical tumor suppressor genes in pathways relevant to GC transformation, differentiation, and treatment response.
Highlights
Human male germ cell tumors (GCTs) arise from undifferentiated primordial germ cells (PGCs), a stage in which extensive methylation reprogramming occurs
Promoter hypermethylation is common in NSGCT and rare in SGCT We assessed 92 GCT DNAs representing all histologic subsets of NSGCT, and SGCT, and four normal testes for methylation status of CpG islands of 21 gene promoters by methylation-specific PCR (MSP) (Fig. 1)
Promoter methylation was frequently seen in DNA repair genes MGMT, RASSF1A, and BRCA1, and a transcriptional repressor gene hypermethylated in cancer 1 (HIC1)
Summary
Human male germ cell tumors (GCTs) arise from undifferentiated primordial germ cells (PGCs), a stage in which extensive methylation reprogramming occurs. Aberrant methylation of CpG islands in promoters is characteristic of several genes in cancer leading to loss of gene expression. The extent of aberrant promoter hypermethylation and its association with loss of gene function in cancer suggests that CpG island methylation is an important mechanism in inactivating tumor suppressor genes (TSGs). GCTs arise by transformation of spermatogonial lineage cells and display pluripotentiality for embryonal and extra-embryonal lineage differentiation [6]. They may present as undifferentiated germ cell (GC)-like seminomas (SGCTs) or highly differentiated nonseminomas (NSGCTs). While the majority of GCTs exhibit exquisite sensitivity to cisplatin-based chemotherapy, a small proportion of metastatic tumors remain resistant. Male GCTs comprise a unique model system to investigate the biology and genetics of GC transformation, differentiation, and chemotherapy resistance/sensitivity [6]
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