TUMOR SUPPRESSORS AND IMPRINTING AT CHROMOSOME 11P155

描述（改编自研究者摘要）： 儿童和成人肿瘤中的杂合性（洛）表明， 染色体带11p15.5含有一个或多个生长或肿瘤抑制因子 基因. 这一概念得到了生长停滞和肿瘤抑制的支持 使用RD和G401细胞杂交功能测定进行的研究。 此外，本发明还提供了一种方法， Beckwith-Wiedemann综合征（BWS; 和长QT综合征地图 到这个地区。 申请人已经隔离了这一重要区域， 在D11 S601和IGF 2/H19之间产生110 -1.1 mb重叠群的PAC克隆。 他们在这个重叠群中定位了9个已知基因， 小说的抄本。 这些新的组织特异性表达模式 基因已通过北方印迹确定。由于该地区是 印迹的，等位基因特异性表达正在通过常规的 方法以及一种新的体细胞杂交试验。 两个新基因 (one其中的印记）是重叠的和发散地转录的， 并在胎儿和成人肝脏中表现出最高水平的表达 使它们成为肿瘤抑制剂的候选者， 肝母细胞瘤和肾母细胞瘤。 三个BWS重排断点 横纹肌样瘤断点被证明会破坏长QT间期 （KVLQT 1）基因。 申请人还表明，其中一个 重排与基因组印记的松弛有关， IGF 2和一种新的差异甲基化CpG岛的识别。 建议研究11p15.5新基因的特征， 与它们在肿瘤中的表达有关。这些基因表现出适当的 将筛选表达谱中的肾母细胞瘤突变， 横纹肌肉瘤与乳腺癌和卵巢癌 候选基因的潜力将在功能测定中进行测试， 在RD和G401细胞中表达。 还建议进行研究， 确定肿瘤和BWS患者的表观遗传变化， 鉴定11 p15印迹癌（IC）。 这些研究将进一步促进我们的 了解癌症的分子病理学，包括 基因组印记的参与。 这些信息可以识别 有价值的预后指标，并将促进更合理的方法 到癌症治疗

DESCRIPTION (Adapted from investigator's abstract): Loss of heterozygosity (LOH) in pediatric and adult tumors indicates that chromosome band 11p15.5 harbors one or more growth or tumor suppressor genes. This notion is supported by growth arrest and tumor suppression studies using RD and G401 cell hybrid functional assays. In addition, the genes responsible for Beckwith-Wiedemann syndrome (BWS; an overgrowth and cancer predisposition disorder) and Long QT syndrome map to this region. The applicants have isolated this important region in PAC clones generating a 1l0-1.1 mb contig between D11S601 and IGF2/H19. They have located nine known genes in this contig and identified 18 novel transcripts. Tissue specific expression patterns of these novel genes have been determined by northern blotting. Since this region is imprinted, allele-specific expression is being assessed by conventional methods as well as a novel somatic cell hybrid assay. Two novel genes (one of which is imprinted) are overlapping and divergently transcribed, and exhibit their highest level of expression in fetal and adult liver and kidney making them candidates for tumor suppressors in hepatoblastoma and Wilms' tumor. Three BWS rearrangement breakpoints and a rhabdoid tumor breakpoint have been shown to disrupt the Long QT (KVLQT1) gene. The applicants also show that one of these rearrangements is associated with relaxation of genomic imprinting at IGF2 and recognition of a novel differentially methylated CpG-island. Studies are proposed to characterize 11p15.5 novel genes with respect to their expression in tumors. Those genes exhibiting an appropriate expression profile will be screened for mutations in Wilms' tumor, rhabdomyosarcomas and breast and ovarian carcinomas The tumor suppressor potential of candidate genes will be tested in a functional assay by expressing them in RD and G401 cells. Studies are also proposed to identify epigenetic changes in tumors and BWS patients as well as to identify a 11p15 imprinting cancer (IC). These studies will further our understanding of the molecular pathology of cancer including the involvement of genomic imprinting. This information may identify valuable prognostic markers and will facilitate more rational approaches to cancer therapies.