Radiation-induced Thyroid Cancer

放射诱发的甲状腺癌

• 批准号: 8138004
• 负责人: Heinz-Ulrich Guenter Weier
• 金额: $ 37.17万
• 依托单位: UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2013-03-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8138004
• 关键词: Accidents; Adult; Age; Archives; Bacterial Artificial Chromosomes; Bioinformatics; Biological Assay; Cancer cell line; Candidate Disease Gene; Cell Line; Cells; Child; Childhood; Chromosomal Rearrangement; Chromosome Band; Chromosome Mapping; Chromosome abnormality; Chromosomes, Human, Pair 10; Collection; Control Groups; Cytogenetics; DNA Probes; DNA Sequence Rearrangement; Databases; Detection; Diagnosis; Diagnostic Neoplasm Staging; Disease; Disease Management; Early Diagnosis; Epithelium; Exhibits; Exposure to; Fluorescent in Situ Hybridization; Frequencies; Future; G-Banding; Genes; Germany; Head and neck structure; Health; Human Genome; In Situ Hybridization; Incidence; Individual; Interphase Cell; Investigation; Ionizing radiation; Karyotype; Karyotype determination procedure; Knowledge; Lead; Life; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of thyroid; Maps; Messenger RNA; Metaphase; Metaphase Spread; Methods; Mitogens; Molecular Genetics; Mutation; Normal tissue morphology; Nuclear Accidents; Nuclear Power Plants; Oncogenes; Oncogenic; Operative Surgical Procedures; PTCH gene; Papillary thyroid carcinoma; Patients; Pattern; Pediatric Neoplasm; Phenotype; Physical Map of the Human Genome; Power Plants; Procedures; Proliferating; Protein Tyrosine Kinase; Radiation; Radiation therapy; Radio; Radioisotopes; Recording of previous events; Regulatory Element; Relative (related person); Research; Resolution; Risk Assessment; Route; Sampling; Screening procedure; Site; Slide; Specimen; Spectral Karyotyping; Stimulus; System; Techniques; Testing; Therapeutic; Therapeutic Intervention; Thyroid Gland; Thyroidectomy; Time; Tissue Sample; Tissues; Transcript; Translocation Breakpoint; Tumor Suppressor Proteins; Tumor Tissue; Tumor stage; USSR; Ukraine; United States Public Health Service; base; carcinogenesis; carcinogenicity; cell preparation; complex biological systems; genetic analysis; genome wide association study; improved; innovation; matrigel; permanent cell line; thyroid neoplasm; tool; tumor

DESCRIPTION (provided by applicant): 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. More than 10 years ago, we and our collaborators in Germany 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 involving chromosome 10. However, many other chPTC tumors have phenotypes not attributable to aberrant ret expression. Instead, most cells showed a normal G-banded karyotype. 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 29 cases of radiation-induced chPTC and identify genes with abnormal pattern of expression. Using a sensitive, genome-wide screening technique termed 'BAC-FISH', which we developed recently, we will localize the breakpoints in 10 radiation-induced tumors (9 chPTC cases and 1 adult case) for which we have cell lines as well as G-banding and Spectral Karyotyping results. With the breakpoints grossly determined, we will prepare breakpoint-spanning BAC contigs and high- resolution physical maps of the rearrangements. Matrigel-based cell invasion assays will provide us with subsets of invasive cells for further cytogenetic studies investigating the presence or absence of structural abnormalities in invasive cells as well as the expression of candidate genes. Next, we will determine the presence or absence of these translocations in 20 additional cases of chPTC for which we already archived metaphase spreads. 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. Additional controls samples will be comprised of thyroid cancer cell lines from patients without a known history of exposure to ionizing radiation. Interphase cell preparations from the control groups will be studied with DNA probes specific for candidate loci to detect rearrangements. For the six most common rearrangements, we will identify genes that map at or near the chromosomal breakpoints using publicly available databases and bioinformatics tools. Finally, we will examine the levels and intracellular localization of potentially oncogenic transcripts (mRNAs) from candidate genes and expressed sequences in the breakpoint regions using multi-target in situ hybridization analyses. PUBLIC HEALTH RELEVANCE: Our innovative screening assay for cryptic translocations is at least one order of magnitude more sensitive than existing tumor karyotyping procedures and might thus provide a wealth of information for a better risk assessment, diagnosis or individualized disease management. Specifically, the proposed studies will help to enhance our understanding of complex biological systems such as the thyroid- specific carcinogenicity of radionuclides. We expect this research to lead to improved control of PTC with regard to early disease detection and better disease management and, thus, to enhance public health services.

描述（由申请人提供）：1986年，苏联切尔诺贝利的核电站发生了一次事故，导致了高水平的放射性同位素的释放。十年后，切尔诺贝利附近的儿童乳头状甲状腺癌（CHPTC）的发生率升高了2个数量级，这很可能是由于增加了电离辐射。辐射产生这些额外的甲状腺癌的途径和机制仍然神秘。十多年前，我们和我们在德国的合作者开始对甲状腺肿瘤组织进行归档，这些患者的甲状腺肿瘤组织在发电厂所在地附近进行了甲状腺切除术，其中包括儿童214个标本。该系列中的几个肿瘤异常表达的RET酪氨酸激酶转录物是由于RET/PTC1或RET/PTC3染色体重排，涉及10染色体。但是，许多其他CHPTC肿瘤具有非异常ret表达的表型。相反，大多数细胞显示出正常的G带核型。此外，即使在RET阳性的CHPTC肿瘤中，并非所有细胞都表达RET或包含10号重排的染色体。我们假设这些其他类别的肿瘤可能不适当地表达了不同的癌基因或由于染色体而失去了肿瘤抑制的功能重排和对导致CHPTC的遗传改变的知识可能有助于早期发现和分期肿瘤，并为治疗干预提供指导。为了检验这一假设，我们建议在29例辐射诱导的CHPTC病例中绘制染色体断点的位点，并鉴定具有异常表达模式的基因。使用一种敏感的，全基因组的筛查技术称为“ BAC-FISH”，我们最近开发了该技术，我们将在10个辐射诱导的肿瘤（9例CHPTC病例和1例成人病例）中定位这些断点，我们有细胞系以及细胞系G带和光谱核分型结果。通过明确确定断点，我们将准备重排的跨断裂BAC重叠群和高分辨率物理图。基于基质的细胞入侵测定法将为我们提供侵入性细胞的亚群，以进一步研究侵入性细胞中结构异常的存在或不存在候选基因的表达。接下来，我们将在20例CHPTC案例中确定这些易位的存在或不存在，我们已经存档中期扩散。对照组将由患有甲状腺癌的儿童组成，而没有事先放射暴露，以及接受放疗的成年患者的肿瘤。其他对照样品将由来自患者的甲状腺癌细胞系组成，而没有已知的电离辐射病史。将使用特异性的候选基因座的DNA探针研究对照组的相间细胞制剂，以检测重排。对于六个最常见的重排，我们将使用公开可用的数据库和生物信息学工具确定在染色体断点或附近映射的基因。最后，我们将使用多目标原位杂交分析来检查候选基因的潜在致癌转录本（mRNA）的水平和细胞内定位，并在断点区域中表达序列。公共卫生相关性：我们对隐秘易位的创新筛查测定法比现有的肿瘤核型型程序更敏感一个数量级，因此可能会提供大量信息，以进行更好的风险评估，诊断或个性化疾病管理。具体而言，拟议的研究将有助于增强我们对复杂生物系统的理解，例如放射性核素的甲状腺特异性致癌性。我们希望这项研究可以改善PTC在早期疾病检测和更好的疾病管理方面的控制，从而改善公共卫生服务。