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
• 负责人: Boris Pasche
• 金额: $ 26.18万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-24 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7189819
• 关键词: Address; Affect; Alanine; Alleles; Amino Acids; Animal Model; Area; Aspirin; Binding; Breast; Cancer Family; Case-Control Studies; Cell surface; Code; Colon; Colon Carcinoma; Colorectal; Colorectal Cancer; Complex; Data; Defect; Disease; Disease Association; Doctor of Philosophy; Dose; Environmental Exposure; Epithelial Cells; Family-Based Registry; Foundations; Frequencies; GCG gene; Gene Frequency; Genes; Genetic; Genetic Polymorphism; Genotype; Genus Cola; Glucagon; Growth; Growth Inhibitors; Haplotypes; Heterozygote; Homozygote; Human; In Vitro; Incidence; Individual; Inherited; Intervention Trial; Laboratories; Lead; Leucine; Ligands; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Medical; Meta-Analysis; Microsatellite Instability; Morbidity - disease rate; Non-Steroidal Anti-Inflammatory Agents; Pathogenesis; Pathway interactions; Patients; Pattern; Penetrance; Positioning Attribute; Predisposition; Principal Investigator; Proline; Registries; Research; Research Personnel; Resources; Risk; Siblings; Signal Pathway; Signal Transduction; TGFB1 gene; TGFBR1 gene; TGFBR2 gene; Testing; Transforming Growth Factor beta; Triplet Multiple Birth; Variant; Work; cancer diagnosis; cancer risk; cancer type; carcinogenesis; case control; cell growth; design; extracellular; gene interaction; genetic epidemiology; in vivo; interest; mortality; neoplasm registry; programs; receptor; receptor binding; tumor

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.

我们之前已经鉴定出 TGFBR1*6A，这是 TGFBR1 基因的常见变体，并表明它传递 TGF-α 生长抑制信号的效率不如 TGFBR1。我们最近的荟萃分析表明，与非携带者相比，TGFBR1*6A 携带者患结肠癌、乳腺癌和卵巢癌的风险显着增加。总体而言，杂合子的癌症风险增加 19%，纯合子的癌症风险增加 70%，这种模式表明等位基因剂量效应。我们还表明 TGFBR1*6A 可能导致遗传性结直肠癌。超过八分之一的健康个体和六分之一的癌症患者是 TGFBR1*6A 携带者，这使 TGFBR1*6A 成为第一个高频低外显率候选肿瘤易感性等位基因。相比之下，在动物模型中，TGF-α循环水平的增加与癌症风险的降低有关。人 TGF-α1 (TGFB1) 基因内第 10 个氨基酸位置变异体中常见的亮氨酸替换为脯氨酸导致体外细胞外 TGFB1 分泌更高。 TGFB1*CC 基因型的携带者比 TGFB1*TT 基因型的携带者具有更高的体内 TGFB1 循环水平。 TGFBR1 和 TGFB1 变体可能对结直肠癌风险具有相反或协同作用。我们的中心假设是，对两种功能相关的 TGF-α 信号通路信号变体进行联合评估将比单独评估每种变体更准确地预测结直肠癌风险。 NCI 赞助的家族性结直肠癌登记处是检验这一假设的理想资源。使用兄弟姐妹匹配的病例对照设计，我们将对总共 4,208 个完整的兄弟姐妹病例对照对进行基因分型，首先：评估 TGFBR1*6A 与结直肠癌之间的关联。第二：评估TGFB1与结直肠癌之间的关联，并对TGFB1基因进行单倍型分析；第三：分析TGFBR1和TGFB1之间的基因间相互作用。这将探索两种功能性 TGF-α 通路多态性与结直肠风险之间的关系，并确定 TGF-α 信号传导是否如这两种变体所预测的那样与结直肠癌风险相关；第四：研究TGF-α通路多态性与肿瘤微卫星不稳定性之间的关系。