Low-Penetrance Genes in the Predisposition to Papillary Thyroid Cancer

低外显率基因易患甲状腺乳头状癌

• 批准号: 8588543
• 负责人: ALBERT DE LA CHAPELLE
• 金额: $ 28.95万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-25 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8588543
• 关键词: 14q; 14q13; 2q35; 8p12; 9q22; Accounting; Alleles; BRAF gene; Binding; Cancer Center; Clinic; Clinical; Clinical Research; Computer Simulation; Data; Diagnosis; Diagnostic; Functional RNA; Generations; Genes; Genetic; Genetic Counseling; Genetic Predisposition to Disease; Genomics; Genotype; Goals; Haplotypes; Instruction; Lead; Learning; Malignant neoplasm of thyroid; Methods; Molecular; Mutation; NRG1 gene; Ohio; Other Genetics; Outcome; Papillary thyroid carcinoma; Pathway interactions; Patients; Penetrance; Pharmaceutical Preparations; Population; Predisposition; Publishing; Reporting; Research; Risk; Series; Somatic Mutation; Staging; Stratification; Susceptibility Gene; TNFRSF5 gene; TNM; Technology; Therapeutic; Thyroid Gland; Translating; Tumor Tissue; Universities; Untranslated RNA; Variant; Work; base; cancer risk; cohort; design; drug development; follow-up; gene discovery; gene interaction; genome wide association study; improved; member; novel; optimism; prevent; research study; risk variant; translational study

The overall goal of this project is to use genetics to improve our chances of preventing, predicting, diagnosing, treating and curing papillary thyroid carcinoma (PTC), which accounts for >80% of all thyroid cancers. Thus far, traditional genetic approaches have failed to pinpoint the culpable predisposing genes. Two genome wide association studies (GWAS) identified five genetic loci associated with highly significant low penetrance predisposition with strong population impact. Two of the pinpointed SNPs reside in conventional translated genes that are pursued elsewhere. Here we focus on the three loci (one in 9q22 and two in 14q13) that are not associated with known genes. Using molecular and in silico methods we have narrowed the regions in which the culpable genomic mutations must reside. In both cases we have identified and delineated novel long intergenic noncoding RNA (lincRNA) genes. These are implicated in the genetic predisposition as shown by their dramatic loss of expression in tumor tissue. These lincRNAs genes are the focus of the first aim of this project. Much more needs to be learned about the mechanistic aspects of the lincRNAs, moreover the culpable genomic mutations must be unequivocally identified. The second aim focuses on translational studies examining the predictive and diagnostic value of the SNPs and the culpable mutations nearby, and their possible association with other genetic/genomic changes in PTC as well as clinical factors and outcome. Our preliminary work has shown that the five available risk SNPs are additive. RELEVANCE (See instructions); The discovery of genes predisposing to PTC and their interaction with other genetic and clinical factors will allow for more accurate genetic counseling, genotype-based risk stratification, and prognostication. Moreover, the elucidation of the genetic pathways leading to PTC will allow therapeutic drugs and preventative strategies to be designed.

这个项目的总体目标是利用遗传学来提高我们预防、预测、 诊断、治疗和治疗甲状腺乳头状癌(PTC)，占所有甲状腺的80% 癌症。到目前为止，传统的遗传学方法还没能准确定位致病基因。 两项全基因组关联研究确定了5个与高度显著相关的遗传位点 外显倾向低，对人口的影响大。其中两个精确定位的SNPs位于 传统的被翻译的基因在其他地方被追求。 在这里，我们重点关注与已知基因无关的三个基因座(一个在9q22，两个在14q13)。 使用分子和电子计算方法，我们已经缩小了罪魁祸首基因组的区域 突变必须存在。在这两种情况下，我们都识别和描绘了新的长基因间非编码 RNA(LincRNA)基因。这些都与遗传易感性有关，表现为它们戏剧性的丢失 在肿瘤组织中的表达。这些lincRNAs基因是这个项目的第一个目标的重点。更多 需要了解lincRNAs的机制方面，以及有责任的基因组 突变必须被明确地识别出来。第二个目标集中在翻译研究上，考察 单核苷酸多态及其附近可致突变的预测和诊断价值及其可能 与PTC的其他遗传/基因组变化以及临床因素和预后的关系。我们的 初步工作表明，五个可用的风险SNPs是相加的。 相关性(见说明)； PTC易感基因的发现及其与其他遗传和临床因素的相互作用将 允许更准确的遗传咨询、基于基因型的风险分层和预测。 此外，阐明导致PTC的遗传途径将使治疗药物和 需要制定预防策略。