TUMOR SUPPRESSORS AND IMPRINTING AT CHROMOSOME 11P155

描述(改编自调查员摘要)：丢失 儿童和成人肿瘤的杂合性(LOH)表明 染色体带11p15.5含有一个或多个生长或肿瘤抑制基因 基因。这一观点得到了生长抑制和肿瘤抑制的支持 应用RD和G401细胞杂交功能分析进行研究。此外, 与Beckwith-Wiedemann综合征(BWS；AN)有关的基因 生长过度和癌症易感性障碍)和长QT间期综合征图 到这个地区。申请者将这一重要地区隔离在 在D11S601和IGF2/H19之间产生110-1.1mb重叠群的PAC克隆。 他们已经在这个重叠群中定位了9个已知基因，并确定了18个 新的成绩单。这些新基因的组织特异性表达模式 基因已经通过Northern blotting确定。因为这个地区是 印记的、等位基因特异性的表达正在通过传统的 方法以及一种新的体细胞杂交分析方法。两个新基因 (其中一个是印记的)是重叠的和不同的转录， 在胎儿和成人肝脏中的表达水平最高 和肾脏使它们成为肿瘤抑制药的候选对象 肝母细胞瘤和肾母细胞瘤。三个BWS重排断点 横纹肌样肿瘤断裂点可以破坏长的QT (KVLQT1)基因。申请者还表明，其中一个 重排与基因组印迹的松弛有关 IGF2和识别一个新的差异甲基化的CpG岛。 建议进行研究，以表征11p15.5个新基因 它们在肿瘤中的表达。这些基因表现出适当的 将对Wilms瘤的表达谱进行突变筛查， 横纹肌肉瘤与抑癌基因乳腺癌和卵巢癌 候选基因的潜力将通过以下方式在功能测试中进行测试 在RD和G401细胞中表达。还建议进行研究，以 确定肿瘤和BWS患者的表观遗传学变化以及 确定11p15印迹癌(IC)。这些研究将进一步推动我们的 对癌症的分子病理学的理解，包括 基因组印迹的参与。该信息可以识别 有价值的预后标志，并将促进更合理的方法 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.