Low-Penetrance Genes in the Predisposition to Papillary Thyroid Cancer

这个项目的总体目标是利用遗传学来提高我们预防，预测， 甲状腺乳头状癌占甲状腺癌的80%以上， 癌的到目前为止，传统的遗传学方法还未能确定罪魁祸首的易感基因。 两项全基因组关联研究（GWAS）确定了与高度显著性相关的五个遗传位点。 具有较强的人口影响的低发病率倾向。两个精确定位的SNP位于 传统的翻译基因在其他地方被追求。 在这里，我们集中在三个位点（一个在9 q22和两个在14 q13），是不相关的已知基因。 使用分子和计算机模拟方法，我们缩小了有罪基因组的区域， 突变必须存在。在这两种情况下，我们已经确定和划定新的长基因间非编码 RNA（lincRNA）基因。这些与遗传易感性有关，如它们的遗传易感性急剧丧失所示。 在肿瘤组织中的表达。这些lincRNA基因是本项目第一个目标的重点。得多 需要了解lincRNA的机制方面，此外， 突变必须被明确识别。第二个目标是翻译研究， SNPs和附近的可归咎突变的预测和诊断价值，以及它们可能的 与PTC中的其他遗传/基因组变化以及临床因素和结果的相关性。我们 初步研究表明，五种可用的风险SNP是相加的。 相关性（参见说明）; 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， 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，导致PTC的遗传途径的阐明将允许治疗药物和 制定预防策略。

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.