Genetic Alterations that Initiate Follicular Thyroid Carcinogenesis

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表达。 在分化型甲状腺癌（DTC）的启动中发挥作用的途径， 通过基因启动的癌症风险评估进行最早诊断。我们将利用人类考登综合征（CS）， 和人类Carney复合体（CNC）的小鼠模型，作为我们的模型的缩影生殖系（遗传） 易感性作为遗传性甲状腺瘤形成疾病启动的第一个事件。CS是一个很难- 识别，诊断不足的遗传性疾病的特点是滤泡性甲状腺腺瘤（FA），DTC和 乳腺癌我们发现，生殖系PTEN突变导致CS和其他临床疾病的有限子集。 综合征，我们统称为PTEN错构瘤-肿瘤综合征（PHTS）。生殖系PRKR 1A 突变与CNC相关。在第一个补助期，我们预期累积了> 3，000名先证者 从社区和学术医疗中心谁符合CS或CS样（CSL）的标准，并创建了一个网络- 基于致病性PTEN突变的存在/不存在和临床 在PHTS中，DTC的终生风险为32%。我们发现了功能性生殖系变异， SDHB和SDHD，编码琥珀酸脱氢酶的2个亚基，导致p53的不稳定， NQ 01和与PTEN核捕获相关的ATP水平降低，我们开发了小鼠模型， FTC的谱，包括FA（甲状腺特异性Pten敲除）、局部侵袭性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 在FTC模型中，我们广泛地假设PTEN，SDHx和PRKR 1A的相互作用起着重要的作用。 通过调节ROS和其他与甲状腺相关的能量学在甲状腺肿瘤形成中起作用。我们将 (1)分析SDHx和PRKARIA生殖系变异，以改变DTC的风险和亚组织学， PTEN突变阳性CS/CSL患者中的其他组分癌症;（2）线粒体能量相关 体外功能测定以分析PTEN和SDHx的相互作用;和（3）生理学验证我们的 在鼠模型中的人体内和体外观察。

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.