Genome-wide methylation profiles in primary intracranial germ cell tumors indicate a primordial germ cell origin for germinomas
Genome-wide methylation profiles in primary intracranial germ cell tumors indicate a primordial germ cell origin for germinomas
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DOI：
10.1007/s00401-017-1673-2
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发表时间：
2017-03-01
影响因子：
12.7
通讯作者：
Ichimura, Koichi
中科院分区：
文献类型：
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作者：
Fukushima, Shintaro;Yamashita, Satoshi;Ichimura, Koichi
颅内生殖细胞肿瘤(IGCT)是日本14岁以下儿童中第二常见的脑肿瘤。世界卫生组织的分类承认了几种iGCT亚型，传统上分为纯性生殖细胞瘤或非生殖细胞性GCT。最近详尽的基因组研究表明，参与MAPK和/或PI3K通路的基因突变在iGCT中很常见；然而，不同亚型如何发展为混合GCT的机制尚不清楚。为了阐明iGCT的发病机制，我们通过全基因组DNA甲基化图谱分析了61个不同亚型的GCT。我们发现，纯性生殖细胞瘤的特征是全球DNA甲基化水平较低，这是一种独特的表观遗传学特征，使它们有别于所有其他iGCT亚型。甲基化模式与迁移阶段的原始生殖细胞(PGC)非常相似，可能表明这些肿瘤的起源细胞。然而，与PGC不同的是，低甲基化延伸到长时间散布的核素反转录转座子。组织学和表观遗传学上不同的混合GCTS的显微解剖成分在MAPK或PI3K途径中具有相同的体细胞突变，表明它们是从共同的祖先细胞发育而来的。
Intracranial germ cell tumors (iGCTs) are the second most common brain tumors among children under 14 in Japan. The World Health Organization classification recognizes several subtypes of iGCTs, which are conventionally subclassified into pure germinoma or non-germinomatous GCTs. Recent exhaustive genomic studies showed that mutations of the genes involved in the MAPK and/or PI3K pathways are common in iGCTs; however, the mechanisms of how different subtypes develop, often as a mixed-GCT, are unknown. To elucidate the pathogenesis of iGCTs, we investigated 61 GCTs of various subtypes by genome-wide DNA methylation profiling. We showed that pure germinomas are characterized by global low DNA methylation, a unique epigenetic feature making them distinct from all other iGCTs subtypes. The patterns of methylation strongly resemble that of primordial germ cells (PGC) at the migration phase, possibly indicating the cell of origin for these tumors. Unlike PGC, however, hypomethylation extends to long interspersed nuclear element retrotransposons. Histologically and epigenetically distinct microdissected components of mixed-GCTs shared identical somatic mutations in the MAPK or PI3K pathways, indicating that they developed from a common ancestral cell.