Molecular Pathology of Solid Tumors in Childhood

我们对胚胎性肿瘤，如生殖细胞肿瘤、Wilms肿瘤和Ewing/PNET肿瘤进行了分子病理分析。1、我们最初从胚胎癌细胞系（NCR-G3）中分离到EAT （all trans - retinoic acid induced early gene by all trans - retinoic acid）基因。测序分析显示，EAT具有BH1和BH2结构域，提示属于bcl家族基因。体外和体内研究表明，该基因具有抗凋亡功能。Northern分析和免疫组织化学研究表明，EAT基因分布于多种胎儿和成人组织，包括早期胚胎发生阶段。通过免疫电镜检查，发现EAT基因只定位于线粒体内外膜。这些发现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，起源于后肾母细胞瘤，是儿童时期最常见的肾脏肿瘤。新基因WT1在染色体11p13区被分离出来，是Wilms肿瘤发生的一个负责基因。该基因在正常肾脏形成和性腺发育，特别是男性生殖器发育中也起重要作用。Denys-Drash综合征以肾母细胞瘤、早发性进行性肾衰竭和泌尿生殖系统异常为特征。最近的研究表明，WT1锌指结构域的外显子突变与该综合征的发病机制有关。我们分析了18例临床诊断为“Denys-Drash”（Drash）综合征的WT1突变。典型Drash综合征9例。而另一些病例则在剪接供体外显子9位点出现了电子点突变。这些突变影响选择性剪接。保留三个氨基酸的同工异构体，KTS，不会产生。内含子突变患者的临床特征与Frasier综合征的临床特征密切相关，其特点是肾病进展比Denys-Drash综合征慢，伴有带状性腺，未发生Wilms肿瘤。我们的研究结果表明，有或没有KTS的WT1亚型在肾脏和性腺的肿瘤发生和器官发生中具有不同的功能。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