RADIATION INDUCED THYROID CANCER

描述：(摘自摘要)1986年，日本一座核电站发生事故 苏联切尔诺贝利核事故导致高水平放射性同位素的释放。十年 后来，儿童乳头状甲状腺癌(ChPTC)的发病率接近 切尔诺贝利已经上升了两个数量级，很可能是因为 暴露于电离辐射的增加。通过哪些途径和机制 辐射产生的这些额外的甲状腺癌仍然是个谜。八 几年前，我们开始对患者的甲状腺肿瘤组织进行存档 在电厂附近进行了甲状腺切除手术，其中214人 来自儿童的标本。这个收集中的几个肿瘤是异常的 Ret/PTC1或ret/PTC3基因转录本的表达 10号染色体上的染色体重排。然而，许多其他chPTC肿瘤 表型不能归因于异常的ret表达。此外，即使是 在ret阳性的chptc肿瘤中，并不是所有细胞都表达ret或含有 10号染色体重排。我们推测这些其他类型的肿瘤可能 不适当地表达不同的癌基因或失去肿瘤功能 染色体重排所致抑制子以及对 导致chPTC的各种基因改变可能有助于早期发现 以及肿瘤的分期，并为治疗干预提供指导。 为了验证这一假设，我们建议绘制染色体断裂点的位置图。 38例辐射诱发的chPTC及其异常基因鉴定 表达的方式。我们将在放射诱导的肿瘤中定位断点 我们用G-显带结果和光谱得到了中期分裂相 核型分析。大致确定了断点后，我们将定义 位置克隆的目标和准备跨越断点的YAC重叠群和 基于共线BAC克隆的高分辨率物理地图。对照组 将由没有事先患上甲状腺癌的儿童组成 接受过放射治疗的成年患者的辐射暴露和肿瘤 儿童或成人接受放射治疗。间期细胞制剂来自于 对照组将通过比较基因组杂交和 用于检测易位和基因的候选基因座的特异性探针 扩增和删除。然后我们可以在chPTC特异的位置识别基因 通过外显子捕获、直接选择和DNA测序获得断裂点。我们会 制备稳定携带致癌重排的细胞系 表征和分配。最后，我们将检查级别和 Northern和原位杂交分析定位mRNAs。

DESCRIPTION: (From Abstract) In 1986, an accident at the nuclear power plant in Chernobyl, USSR, led to the release of high levels of radioisotopes. Ten years later, the incidence of childhood papillary thyroid cancer (chPTC) near Chernobyl had risen by 2 orders of magnitude, most likely as a consequence of increased exposure to ionizing radiation. The routes and mechanisms by which radiation generated these additional thyroid cancers remain mysterious. Eight years ago, we began to archive thyroid tumor tissues from patients who underwent thyroidectomy near the site of the power plant, among them 214 specimens from children. Several tumors from this collection aberrantly expressed ret tyrosine kinase transcripts due to a ret/PTC1 or ret/PTC3 chromosomal rearrangements on chromosome 10. However, many other chPTC tumors have phenotypes not attributable to aberrant ret expression. Moreover, even within a ret-positive chPTC tumor, not all cells express ret or contain a rearranged chromosome 10. We hypothesize that these other classes of tumors may inappropriately express a different oncogene or have lost function of a tumor suppressor as a result of chromosomal rearrangements and that knowledge of the kind of genetic alterations leading to chPTC may facilitate the early detection and staging of tumors as well as provide guidance for therapeutic intervention. To test this hypothesis, we propose to map the sites of chromosomal breakpoints in 38 cases of radiation-induced chPTC and identify genes with abnormal pattern of expression. We will localize the breakpoints in radiation-induced tumors for which we have metaphase spreads using G-banding results and Spectral Karyotyping. With the breakpoints grossly determined, we will define the targets for positional cloning and prepare breakpoint-spanning YAC contigs and high-resolution physical maps based on co-linear BAC clones. Control groups will be comprised of children who developed thyroid cancer without prior radiation exposure as well as tumors in adult patients who underwent radiotherapy as children or adults. Interphase cell preparations from the control groups will be studied with comparative genomic hybridization and probes specific for candidate loci to detect translocations as well as gene amplifications and deletions. We can then identify genes at the chPTC-specific breakpoints by exon-trapping, direct selection, and DNA sequencing. We will prepare stable cell lines carrying the oncogenic rearrangements for further characterization and distribution. Finally, we will examine the levels and localization of mRNAs with Northern and in situ hybridization analysis.