TGF-beta pathway polymorphisms and colon cancer risk
TGF-β途径多态性与结肠癌风险
基本信息
- 批准号:7350209
- 负责人:
- 金额:$ 12.65万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2006
- 资助国家:美国
- 起止时间:2006-02-24 至 2008-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAlanineAllelesAmino AcidsAnimal ModelAreaAspirinBindingBreastCancer FamilyCase-Control StudiesCell surfaceCodeColonColon CarcinomaColorectalColorectal CancerComplexDataDefectDiseaseDisease AssociationDoctor of PhilosophyDoseEnvironmental ExposureEpithelial CellsFamily-Based RegistryFoundationsFrequenciesGCG geneGene FrequencyGenesGeneticGenetic PolymorphismGenotypeGenus ColaGlucagonGrowthGrowth InhibitorsHaplotypesHeterozygoteHomozygoteHumanIn VitroIncidenceIndividualInheritedIntervention TrialLaboratoriesLeadLeucineLigandsMalignant NeoplasmsMalignant neoplasm of ovaryMediatingMedicalMeta-AnalysisMicrosatellite InstabilityMorbidity - disease rateNon-Steroidal Anti-Inflammatory AgentsPathogenesisPathway interactionsPatientsPatternPenetrancePositioning AttributePredispositionPrincipal InvestigatorProlineRegistriesResearchResearch PersonnelResourcesRiskSiblingsSignal PathwaySignal TransductionTGFB1 geneTGFBR1 geneTGFBR2 geneTestingTransforming Growth Factor betaTriplet Multiple BirthVariantWorkcancer diagnosiscancer riskcancer typecarcinogenesiscase controlcell growthdesignextracellulargene interactiongenetic epidemiologyin vivointerestmortalityneoplasm registryprogramsreceptorreceptor bindingtumor
项目摘要
We have previously identified TGFBR1*6A, a common variant of the TGFBR1 gene, and shown that it transmits TGF-a growth inhibitory signals less effectively than TGFBR1. Our recent meta-analyses show that TGFBR1*6A carriers have a significantly increased risk of colon, breast and ovarian cancer as compared with non-carriers. Overall, cancer risk is increased by 19% among heterozygotes and 70% among homozygotes, a pattern indicative of an allelic dosing effect. We have also shown that TGFBR1*6A may contribute to hereditary colorectal cancer. More than one in eight healthy individuals and one in six patients with cancer is a TGFBR1*6A carrier, which establishes TGFBR1*6A as the first high-frequency low-penetrance candidate tumor susceptibility allele. In contrast, increased TGF-a circulating levels have been associated with a decreased cancer risk in animal models. A common Leucine to Proline substitution at the 10th amino acid position variant within the human TGF- a1 (TGFB1) gene results in higher in vitro extracellular TGFB1 secretion. Carriers of the TGFB1*CC genotype have higher in vivo TGFB1 circulating levels than carriers of the TGFB1*TT genotype. TGFBR1 and TGFB1 variants my have opposite or synergistic effects on colorectal cancer risk. Our central hypothesis is that a combined assessment of the two functionally-relevant TGF- a pathway signaling variants will predict colorectal cancer risk more accurately than each variant alone. The NCI-sponsored familial colorectal cancer registry is an ideal resource in which to test this hypothesis. Using a sibling-matched case-control design we will genotype a total of 4,208 full sibling case-control pairs and First: assess the association between TGFBR1*6A and colorectal cancer. Second: assess the association between TGFB1 and colorectal cancer and perform haplotype analysis of the TGFB1 gene; Third: analyze gene-gene interactions between TGFBR1 and TGFB1. This will explore the relationships between the two functional TGF-a pathway polymorphisms and colorectal risk and determine whether TGF- a signaling, as predicted by these two variants, is associated with colorectal cancer risk; and, Fourth: investigate the relationship between TGF-a pathway polymorphisms and tumor microsatellite instability.
我们先前已经鉴定出TGFBR1*6A是TGFBR1基因的常见变体,并表明它的传输TGF-A生长抑制信号的有效性比TGFBR1有效。我们最近的荟萃分析表明,与非携带者相比,TGFBR1*6A携带者患结肠,乳腺癌和卵巢癌的风险显着增加。总体而言,杂合子中的癌症风险增加了19%,纯合子中的风险增加了70%,这种模式表明了等位基因剂量作用。我们还表明,TGFBR1*6A可能导致遗传性结直肠癌。 TGFBR1*6A携带者是八分之一的健康个体和六分之一的癌症患者,该携带者将TGFBR1*6A建立为第一个高频低频率候选肿瘤易感性等位基因。相比之下,TGF-A循环水平的提高与动物模型的癌症风险降低有关。在人TGF-A1(TGFB1)基因中第10个氨基酸位置变体中脯氨酸取代的常见亮氨酸导致体外细胞外TGFB1分泌。 TGFB1*CC基因型的载体在体内TGFB1循环水平高于TGFB1*TT基因型的载体。我的TGFBR1和TGFB1变体对结直肠癌的风险有相反或协同作用。我们的中心假设是,对两个与功能相关的TGF- A途径信号变异的组合评估将比单独的每个变体更准确地预测结直肠癌的风险。 NCI赞助的家族性大肠癌注册中心是检验该假设的理想资源。使用兄弟姐妹匹配的病例对照设计,我们将共同基因型4,208个完整的兄弟姐妹病例对照对,首先:评估TGFBR1*6A与结直肠癌之间的关联。第二:评估TGFB1与大肠癌之间的关联,并对TGFB1基因进行单倍型分析;第三:分析TGFBR1和TGFB1之间的基因基因相互作用。这将探讨两个功能性TGF-A途径多态性和结直肠风险之间的关系,并确定这两个变体所预测的TGF- A信号是否与大肠癌风险有关; ,第四:研究TGF-A途径多态性与肿瘤微卫星不稳定性之间的关系。
项目成果
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Boris Pasche其他文献
Boris Pasche的其他文献
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{{ truncateString('Boris Pasche', 18)}}的其他基金
Administrative Supplements for the NCI P30 Cancer Center Support Grants for Multi-Channel Communication Campaigns for Improvements in Cancer Education and Outcomes (MICEO) in Underserved Populations
NCI P30 癌症中心行政补充,支持多渠道沟通活动,以改善服务不足人群的癌症教育和结果 (MICEO)
- 批准号:
10891877 - 财政年份:2022
- 资助金额:
$ 12.65万 - 项目类别:
Role of TGF-Beta Genetic Variants in the Pathogenesis of Scleroderma
TGF-β 基因变异在硬皮病发病机制中的作用
- 批准号:
7665023 - 财政年份:2008
- 资助金额:
$ 12.65万 - 项目类别:
Role of TGF-Beta Genetic Variants in the Pathogenesis of Scleroderma
TGF-β 基因变异在硬皮病发病机制中的作用
- 批准号:
7267285 - 财政年份:2007
- 资助金额:
$ 12.65万 - 项目类别:
TGF-beta pathway polymorphisms and colon cancer risk
TGF-β途径多态性与结肠癌风险
- 批准号:
7189819 - 财政年份:2006
- 资助金额:
$ 12.65万 - 项目类别:
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