Genetic Alterations that Initiate Follicular Thyroid Carcinogenesis

引发滤泡性甲状腺癌的基因改变

基本信息

批准号：
8697754
负责人：
Charis Eng
金额：
$ 40.75万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-03-01 至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8697754
关键词：
Academic Medical Centers Address Alleles Atrial myxoma with lentigines Biological Assay Cancer Histology Cells Characteristics Clinical Clinical Management Communities Data Development Diagnosis Disease Down-Regulation Early Diagnosis Epithelial Event Family member Follicular Adenoma Gene Mutation Genes Genetic Genetic Predisposition to Disease Genetic Risk Germ-Line Mutation Grant Hamartoma Histology Human In Vitro Incidence Individual Inherited Instruction Knock-out Lead Logistic Regressions Malignant Neoplasms Malignant neoplasm of thyroid Mitochondria Modeling Multiple Hamartoma Syndrome Mus Mutate Mutation Neoplasms Nuclear Online Systems PTEN gene Papillary Pathway interactions Patients Physiological Play Predisposition Prevalence Production Research Personnel Risk Risk Assessment Role Series Signal Pathway Succinate Dehydrogenase Susceptibility Gene Syndrome Testing Thyroid Gland Validation Variant base cancer initiation cancer risk carcinogenesis in vivo lifetime risk malignant breast neoplasm meetings mouse model mutation carrier proband promoter tumor

项目摘要

Project 2 takes a clinical and translational genetics approach to identify and characterize genes and their pathways that play a role In the initiation of differentiated thyroid cancer (DTC) for the purposes of the eariiest diagnosis via gene-enabled cancer risk assessment. We will utilize human Cowden syndrome (CS), and a mouse model of human Carney Complex (CNC), as our models epitomizing germline (inherited) predisposition as the first event in initiation in a heritable thyroid neoplasia disorder. CS is a difficult-to- recognize, under-diagnosed heritable disorder characterized by follicular thyroid adenomas (FA), DTC and breast cancer. We found that germline PTEN mutations cause finite subsets of CS and other clinical syndromes, which we collectively term PTEN hamartoma-tumor syndrome (PHTS). Germline PRKR1A mutations associate with CNC. In the first grant period, we have prospectively accrued >3,000 probands from community and academic medical centers who meet CS or CS-like (CSL) criteria and created a web- based PTEN risk calculator based on presence/absence of pathogenic PTEN mutations and clinical characteristics; and showed 32% lifetime risk of DTC in PHTS. We found functional germline variants in SDHB and SDHD, encoding 2 subunits of succinate dehydrogenase, resulting in destabilization of p53 via NQ01 and decreasing ATP levels associated with PTEN nuclear trapping, we developed mouse models of the spectrum of FTC, including FA (thyroid-specific Pten knock-out), locally invasive FTC (Prkaria KO), and metastatic FTC (Pten/Prkaria double KO); preliminary data Indicating downregulation of Sdhb and other Sdh subunits in the FTC models, we broadly hypothesize that Interactions of PTEN, SDHx and PRKR1A play a role in thyroid neoplasia initiation by modulating ROS and other mitochondria-associated energetics. We will (1) analyze SDHx and PRKARIA germline variants In modifying the risk and sub-histology of DTC and of other component cancers in PTEN mutation positive CS/CSL patients; (2) mitochondrial energetics-relevant in vitro functional assays to analyse the interaction of PTEN and SDHx; and (3) physiological validate our human in vivo and in vitro observations in murine models.

项目 2 采用临床和转化遗传学方法来识别和表征基因及其特征出于以下目的，在分化型甲状腺癌 (DTC) 的发生中发挥作用的途径通过基因驱动的癌症风险评估进行最早的诊断。我们将利用人类考登综合症（CS），以及人类卡尼复合物 (CNC) 的小鼠模型，作为我们的模型的种系（遗传）的缩影易感性是遗传性甲状腺肿瘤疾病起始的第一个事件。 CS是一个很难识别以滤泡性甲状腺腺瘤 (FA)、DTC 和乳腺癌。我们发现种系 PTEN 突变导致 CS 和其他临床症状的有限子集综合征，我们统称为 PTEN 错构瘤肿瘤综合征 (PHTS)。种系PRKR1A 突变与 CNC 相关。在第一个资助期内，我们预计已积累了超过 3,000 名先证者来自符合 CS 或类 CS (CSL) 标准的社区和学术医疗中心，并创建了一个网络- 基于 PTEN 风险计算器，基于致病性 PTEN 突变的存在/不存在和临床特征; PHTS 患者终生罹患 DTC 的风险为 32%。我们发现了功能性种系变异 SDHB 和 SDHD，编码琥珀酸脱氢酶的 2 个亚基，通过以下方式导致 p53 不稳定 NQ01 和与 PTEN 核捕获相关的 ATP 水平降低，我们开发了以下小鼠模型 FTC 谱系，包括 FA（甲状腺特异性 Pten 敲除）、局部侵入性 FTC（Prkaria KO）和转移性 FTC（Pten/Prkaria 双 KO）；初步数据表明 Sdhb 和其他 Sdh 下调对于 FTC 模型中的亚基，我们广泛假设 PTEN、SDHx 和 PRKR1A 的相互作用发挥着通过调节 ROS 和其他线粒体相关能量在甲状腺肿瘤发生中发挥作用。我们将 (1) 分析 SDHx 和 PRKARIA 种系变异改变 DTC 的风险和亚组织学 PTEN 突变阳性 CS/CSL 患者的其他癌症； (2) 线粒体能量学相关体外功能测定分析 PTEN 和 SDHx 的相互作用； (3)生理验证我们的人类在小鼠模型中的体内和体外观察。