RADIATION INDUCED THYROID CANCER

描述：（摘自摘要）1986年， 前苏联切尔诺贝利核电站导致大量放射性同位素的释放。十年 后来，儿童甲状腺乳头状癌（chPTC）的发病率接近 切尔诺贝利上升了两个数量级，很可能是由于 增加电离辐射暴露。其途径和机制， 这些额外的甲状腺癌产生的辐射仍然是个谜。八 几年前，我们开始存档甲状腺肿瘤组织， 在发电厂附近接受甲状腺切除术，其中214人 儿童标本。这个标本中的几个肿瘤 由于ret/PTC 1或ret/PTC 3， 10号染色体上的染色体重排然而，许多其他chPTC肿瘤 具有不归因于异常ret表达的表型。而且就算 在ret阳性的chPTC肿瘤中，并非所有细胞都表达ret或含有 重排的10号染色体我们假设这些其他类型的肿瘤可能 不适当地表达不同癌基因或已经丧失肿瘤功能 由于染色体重排和对基因突变认识， 一种导致chPTC的遗传改变可能有助于早期发现 和肿瘤分期以及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 对38例放射性chPTC患者进行基因分型，并对分型异常的基因进行鉴定 的表达。我们将定位放射诱导肿瘤的断裂点， 我们用G-显带结果和光谱分析 核型分析。在大致确定断点后，我们将定义 用于定位克隆的靶并制备跨越断点的YAC重叠群， 基于共线BAC克隆的高分辨率物理图。对照组 将由患有甲状腺癌的儿童组成， 在接受放射治疗的成年患者中， 儿童或成人的放射治疗。间期细胞制备， 对照组将用比较基因组杂交进行研究， 特异于候选基因座的探针，以检测易位以及基因 扩增和缺失。然后我们可以在chPTC特异性 通过外显子捕获、直接选择和DNA测序来检测断裂点。我们将 制备携带致癌重排的稳定细胞系， 特征和分布。最后，我们将检查水平和 用北方和原位杂交分析定位mRNA。

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.