Koul Sanjay, Houldsworth Jane, Mansukhani Mahesh M, Donadio Alessia, McKiernan James M, Reuter Victor E, Bosl George J, Chaganti Raju S, Murty Vundavalli V
Department of Pathology, College of Physicians & Surgeons of Columbia University, 630 West 168th Street, New York, NY, 10032, USA.
Mol Cancer. 2002 Nov 28;1:8. doi: 10.1186/1476-4598-1-8.
Human male germ cell tumors (GCTs) arise from undifferentiated primordial germ cells (PGCs), a stage in which extensive methylation reprogramming occurs. GCTs exhibit pluripotentiality and are highly sensitive to cisplatin therapy. The molecular basis of germ cell (GC) transformation, differentiation, and exquisite treatment response is poorly understood.
To 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 occurred upon treatment with 5-Aza-2' deoxycytidine in GCT cell lines.
Our results, therefore, suggest a potential role for epigenetic modification of critical tumor suppressor genes in pathways relevant to GC transformation, differentiation, and treatment response.
人类男性生殖细胞肿瘤（GCTs）起源于未分化的原始生殖细胞（PGCs），这是一个发生广泛甲基化重编程的阶段。GCTs具有多能性，对顺铂治疗高度敏感。生殖细胞（GC）转化、分化及对治疗的精准反应的分子基础尚不清楚。
为评估启动子高甲基化的作用和机制，我们通过甲基化特异性PCR分析了精原细胞瘤（SGCT）和非精原细胞瘤（NSGCT）GCTs中21个基因启动子的CpG岛。我们发现60%的NSGCTs在一个或多个基因启动子中表现出甲基化，而SGCTs几乎没有甲基化，因此在GCT的两种主要组织学类型中确定了不同的甲基化模式。DNA修复基因MGMT、RASSF1A和BRCA1以及转录抑制基因HIC1在NSGCTs中频繁甲基化。启动子高甲基化与大多数甲基化基因的基因沉默相关，在用5-氮杂-2'-脱氧胞苷处理GCT细胞系后基因表达重新激活。
因此，我们的结果表明关键肿瘤抑制基因的表观遗传修饰在与GC转化、分化及治疗反应相关的途径中具有潜在作用。
