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.

该项目的总体目标是使用遗传学来提高我们预防，预测，预测， 诊断，治疗和治疗乳头状甲状腺癌（PTC），占甲状腺均> 80％ 癌症。迄今为止，传统的遗传方法未能确定易于诱惑的基因。 两项基因组广泛的关联研究（GWAS）确定了与高度显着相关的五个遗传基因座 低渗透率易受影响，人口影响很强。两个精确的SNP位于 传统的翻译基因在其他地方进行。 在这里，我们专注于与已知基因无关的三个基因座（第9季度和第14季度的两个基因座）。 使用分子和计算机方法，我们缩小了可屈服基因组的区域 突变必须存在。在这两种情况下 RNA（lincRNA）基因。这些与遗传倾向有关，如它们的戏剧性丧失所示 在肿瘤组织中的表达。这些LincrNA基因是该项目的第一个目的的重点。更多 此外，需要了解Lincrnas的机械方面 必须明确鉴定突变。第二个目的侧重于转化研究 SNP的预测和诊断价值和附近的可判性突变及其可能 与PTC的其他遗传/基因组变化以及临床因素和结果相关。我们的 初步工作表明，可用的五种风险SNP是加性的。 相关性（请参阅说明）； 发现易感PTC的基因及其与其他遗传和临床因素的相互作用将会 允许更准确的遗传咨询，基于基因型的风险分层和预后。 此外，阐明导致PTC的遗传途径将允许治疗药物和 设计的预防策略。