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:8505981
- 负责人:
- 金额:$ 41.85万
- 依托单位:
- 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:
- 关键词:Academic Medical CentersAddressAllelesAtrial myxoma with lentiginesBiological AssayCancer HistologyCellsCharacteristicsClinicalClinical ManagementCommunitiesDataDevelopmentDiagnosisDiseaseDown-RegulationEarly DiagnosisEpithelialEventFamily memberFollicular AdenomaGene MutationGenesGeneticGenetic Predisposition to DiseaseGenetic RiskGerm-Line MutationGrantHamartomaHistologyHumanIn VitroIncidenceIndividualInheritedInstructionKnock-outLeadLogistic RegressionsMalignant NeoplasmsMalignant neoplasm of thyroidMitochondriaModelingMultiple Hamartoma SyndromeMusMutateMutationNeoplasmsNuclearOnline SystemsPTEN genePapillaryPathway interactionsPatientsPhysiologicalPlayPredispositionPrevalenceProductionResearchResearch PersonnelRiskRisk AssessmentRoleSeriesSignal PathwaySuccinate DehydrogenaseSusceptibility GeneSyndromeTestingThyroid GlandValidationVariantbasecancer initiationcancer riskcarcinogenesisin vivolifetime riskmalignant breast neoplasmmeetingsmouse modelmutation carrierprobandpromotertumor
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.
RELEVANCE (See instructions):
Compared to 1 % lifetime risk of developing thyroid cancer, individuals who are at genetic risk carry markedly
increased (but never 100%) lifetime risks, often eariy-onset, multifocal and aggressive, and more importantly,
almost always carry risks of other extra-thyroldal cancers. However, what remains elusive is the ability to
predict which individual carrying predisposition alleles will develop a component malignancy, in this case,
DTC. We propose to study energetics for modifying heritable thyroid cancer risk and histology
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其特征
出于分化甲状腺癌(DTC)的作用的途径
通过支持基因的癌症风险评估,最新的诊断。我们将利用人类Cowden综合征(CS),
和人类Carney复合物(CNC)的小鼠模型,因为我们的模型表现出缩影(继承)
易感性是雄性甲状腺肿瘤疾病中的第一个事件。 CS很难
认识到,以卵泡甲状腺腺瘤(FA),DTC和
乳腺癌。我们发现种系PTEN突变会导致CS和其他临床的有限子集
综合征,我们共同将其称为PTEN Hamartoma肿瘤综合征(PHTS)。种系PRKR1A
与CNC相关的突变。在第一个赠款期间,我们预期累积了> 3,000个概率
来自符合CS或类似CS的(CSL)标准并创建网络的社区和学术医疗中心
基于病原PTEN突变和临床的存在/不存在基于PTEN风险计算器
特征;并显示出PHT中DTC的终身风险32%。我们在
SDHB和SDHD,编码2个琥珀酸酯脱氢酶的亚基,导致p53通过
NQ01和与PTEN核捕获相关的ATP水平降低,我们开发了小鼠模型
FTC的光谱,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的下调
FTC模型中的亚基,我们广泛地假设PTEN,SDHX和PRKR1A的相互作用播放
通过调节ROS和其他与线粒体相关的能量学调节甲状腺肿瘤的起始。我们将
(1)分析SDHX和Prkaria种系变体,以修改DTC的风险和次级学
PTEN突变阳性CS/CSL患者中的其他成分癌症; (2)线粒体与能量相关
体外功能分析以分析PTEN和SDHX的相互作用; (3)生理验证我们的
人体体内和鼠模型中的体外观察结果。
相关性(请参阅说明):
与患甲状腺癌的终身风险相比,处于遗传风险的人持有明显的
终生风险(但从未有100%)增加,通常发作,多焦点和侵略性,更重要的是
几乎总是承担其他胸外癌的风险。但是,仍然难以捉摸的是能力
预测哪种携带倾向等位基因将产生成分恶性肿瘤,在这种情况下,
DTC。我们建议研究用于修改可遗传甲状腺癌风险和组织学的能量学
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Charis Eng其他文献
Charis Eng的其他文献
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{{ truncateString('Charis Eng', 18)}}的其他基金
The 6th Annual International PTEN Symposium: From Patient-Centered Research to Clinical Care
第六届国际 PTEN 研讨会:从以患者为中心的研究到临床护理
- 批准号:
10683454 - 财政年份:2023
- 资助金额:
$ 41.85万 - 项目类别:
Modeling Autism and Comorbid Cancer Risk in Individuals with Germline PTEN Mutations
种系 PTEN 突变个体的自闭症和共病癌症风险建模
- 批准号:
10704496 - 财政年份:2022
- 资助金额:
$ 41.85万 - 项目类别:
Modeling Autism and Comorbid Cancer Risk in Individuals with Germline PTEN Mutations
种系 PTEN 突变个体的自闭症和共病癌症风险建模
- 批准号:
10358435 - 财政年份:2022
- 资助金额:
$ 41.85万 - 项目类别:
Natural history of individuals with autism spectrum disorder and germline PTEN mutations
患有自闭症谱系障碍和种系 PTEN 突变的个体的自然史
- 批准号:
10242080 - 财政年份:2014
- 资助金额:
$ 41.85万 - 项目类别:
Natural history of individuals with autism spectrum disorder and germline PTEN mutations
患有自闭症谱系障碍和种系 PTEN 突变的个体的自然史
- 批准号:
10701741 - 财政年份:2014
- 资助金额:
$ 41.85万 - 项目类别:
Deep Sequencing Instrumentation Upgrade - Illumina HiSeq2500
深度测序仪器升级 - Illumina HiSeq2500
- 批准号:
8640603 - 财政年份:2014
- 资助金额:
$ 41.85万 - 项目类别:
Metagenomic profiling of oral polymicrobial flora in head and neck cancers
头颈癌口腔多微生物菌群的宏基因组分析
- 批准号:
8142045 - 财政年份:2010
- 资助金额:
$ 41.85万 - 项目类别:
Genetic Alterations that Initiate Follicular Thyroid Carcinogenesis
引发滤泡性甲状腺癌的基因改变
- 批准号:
8697754 - 财政年份:2008
- 资助金额:
$ 41.85万 - 项目类别:
Genetic Alterations that Initiate Follicular Thyroid Carcinogenesis
引发滤泡性甲状腺癌的基因改变
- 批准号:
9041528 - 财政年份:2008
- 资助金额:
$ 41.85万 - 项目类别:
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