Characteristic promoter hypermethylation signatures in male germ cell tumors.
Characteristic promoter hypermethylation signatures in male germ cell tumors.
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DOI：
10.1186/1476-4598-1-8
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发表时间：
2002-11-28
期刊：
影响因子：
37.3
通讯作者：
Murty, Vundavalli V
中科院分区：
文献类型：
--
作者：
Koul, Sanjay;Houldsworth, Jane;Murty, Vundavalli V
背景：人类男性生殖细胞肿瘤（gct）起源于未分化的原始生殖细胞（PGCs），这一阶段发生了广泛的甲基化重编程。gct表现出多能性，对顺铂治疗高度敏感。生殖细胞（GC）转化、分化和治疗反应的分子基础尚不清楚。结果：为了评估启动子超甲基化的作用和机制，我们通过甲基化特异性PCR分析了21个基因启动子在半胱氨酸瘤（SGCT）和非半胱氨酸瘤（NSGCT） gct中的CpG岛。我们发现60%的nsgct在一个或多个基因启动子中显示甲基化，而sgct显示几乎没有甲基化，因此在GCT的两种主要组织学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nsgct中经常甲基化。在大多数甲基化基因中，启动子超甲基化与基因沉默有关，在GCT细胞系中，5-Aza-2'脱氧胞苷处理后，基因表达发生再激活。结论：因此，我们的研究结果表明，关键肿瘤抑制基因的表观遗传修饰在与胃癌转化、分化和治疗反应相关的途径中具有潜在作用。
BACKGROUND: 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.RESULTS: 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.CONCLUSIONS: 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.