Molecular Pathology of Solid Tumors in Childhood

我们对胚胎性肿瘤如生殖细胞瘤、Wilms瘤和Ewing/PNET瘤进行了分子病理学分析，这些肿瘤被认为是在胚胎组织中产生的。1.我们最初从胚胎性癌细胞系（NCR-G3）中分离EAT（early gene induced by all transretinoic acid）基因。序列分析显示EAT具有BH 1和BH 2结构域，提示其为bcl家族基因。体外和体内研究表明，该基因具有抗凋亡功能。北方分析和免疫组化研究表明，EAT基因分布于胚胎发育早期的多种组织中。免疫电镜结果显示EAT基因仅定位于线粒体的外膜和内膜。这些结果表明，该基因通过抗凋亡功能在维持早期胚胎发生中起重要作用。2，肾母细胞瘤是一种典型的胚胎性肿瘤， 关于我们 来源于后肾母细胞瘤和儿童期最常见的肾脏肿瘤。WT 1基因是从染色体11 p13区域分离到的一个与肾母细胞瘤发生有关的基因。该基因还在正常的肾发生和性腺发育，特别是男性生殖器官发育中发挥重要作用。Denys-Drash综合征，特征为肾母细胞瘤、早发性和进行性肾衰竭以及泌尿生殖系统异常。近年来的研究表明，WT 1基因锌指结构域外显子突变与该综合征的发病有关。我们分析了18例临床诊断为“Denys-Drash”（Drash）综合征病例的WT 1突变。9例为典型Drash综合征。另1例在外显子9的剪接供体位点发生慢性点突变。这些突变影响选择性剪接。不产生保留三个氨基酸的同种型KTS。具有内含子突变的患者的临床特征与Frasier综合征的临床特征相关性良好，Frasier综合征的特征是比Denys-Drash综合征更缓慢进展的肾病，相关的条纹性腺，并且没有Wilms肿瘤的发展。我们的研究结果表明，WT 1亚型与或没有KTS有不同的功能，在肿瘤的发生和器官的肾脏和性腺。少

We performed molecular pathological analysis of embryonal tumors such as germ cell tumors, Wilms tumors and Ewing/PNET tumors which are thought to be derived from embryonal tissue during.1, we originally isolated EAT (early gene induced by all trans retinoic acid) gene from embryonal carcinoma cell lines (NCR-G3). Sequencing analysis revealed that EAT possessed BH1 and BH2 domains suggesting a bcl family gene. This gene was shown to have antiapoptotic functions by vitro and in vivo studies. Northern analysis and immunohistochemical studies disclosed that he EAT gene distributed in a variety of fetal and adult tissues including stage of early embryogenesis. EAT gene was shown to exclusively localize in the external and internal membrane of mitochondria by using immunoelectron microscopic procedures. These findings suggested that this gene play an important role in maintenance of early embryogenesis through antiapoptotic functions.2, Wilms tumor are a typical embryonal tumors that is der … More ived from metanephric blastoma and the most common renal tumors in childhood. Novel gene, WT1, has been isolated chromosome11p13 region as a responsible gene in oncogenesis of Wilms tumor. This gene also play an important role in normal nephrogenesis and gonadal developments, especially male genital organs. Denys-Drash syndrome characterized by association of Wilms tumor, early onset and progressive renal failure and urogenital anomalies. Recent studies showed that exonic mutations at zinc finger domains of WT1 is responsible for pathogenesis of this syndrome. We analyzed WT1 mutations in 18 clinically diagnosed "Denys-Drash"(Drash) syndrome cases. 9 cases were typical Drash syndrome. Whereas another cases showed inronic point mutations at the splicing donor site at exon9. These mutations affect alternative splicing. The isoforms retaining three amino acids, KTS, are not produced. Clinical features of the patients with the intronic mutations correlated well with those of Frasier syndrome, characterized by more slowly progressing nephropathy than Denys-Drash syndrome, associated streak gonads and no development of Wilms' tumor. Our results indicate that WT1 isoforms with or without KTS have different functions in tumorigenesis and organogenesis of kidneys and gonads. Less