TGF-beta pathway variants and breast cancer in families

描述(申请人提供)：我们首次鉴定出TGFBR1*6A，一种常见的TGFBR1基因变体(编码I型转化生长因子-β受体)。我们已经证明，TGFBR1*6A传递转化生长因子-β生长抑制信号的效率明显低于TGFBR1。在对发表在TGFBR1*6A上的3项病例对照研究(包括555例病例和1033例对照)的荟萃分析中，21.1%的病例和13.6%的对照是TGFBR1*6A携带者，TGFBR1*6A与乳腺癌显著相关(OR1.48，CI 1.11-1.96)。人转化生长因子-β1(TGFB1)基因本身的一个常见变异是第10位氨基酸(T29C)上亮氨酸(T-C)被取代。在携带C等位基因的人中，T-&GT；C替换导致细胞外TGFB1分泌增加，循环中TGFB1水平增加。关于乳腺癌风险的这种多态研究得出了相互矛盾的结果。我们建议通过一项基于家庭的关联研究，比较1844名乳腺癌患者和她们2547名未受影响的姐妹的基因类型，来评估这两个具有良好特征和功能相关的转化生长因子-β信号通路变异与乳腺癌风险之间的单独和联合关联。我们有以下具体目标： 1)探讨TGFBR1*6A等位基因携带者状态与乳腺癌风险的关系。假设：该等位基因的携带者状态与乳腺癌风险增加有关。2)评估转化生长因子-β信号通路的另一个功能相关变体TGFB1 T29C与乳腺癌风险之间的关系。假设：T等位基因的携带者状态与乳腺癌风险增加有关。 3)评估影响转化生长因子-β信号转导的TGFBR1和TGFB1变异对乳腺癌风险的联合作用。假设：与转化生长因子-β信号转导预测水平最低的个体，即携带TGFB1*T等位基因和TGFBR1*6A等位基因的个体相比，携带TGFB1*T等位基因和TGFBR1*6A等位基因的个体患乳腺癌的风险更高。

DESCRIPTION (provided by applicant): We were the first to identify TGFBR1*6A, a common variant of the TGFBR1 gene (which encodes the type I TGF-beta receptor). We have shown that TGFBR1*6A transmits TGF-beta growth inhibitory signals significantly less effectively than does TGFBR1. In a meta-analysis of the three case-control studies published on TGFBR1*6A and breast cancer that include 555 cases and 1033 controls, 21.1% of cases and 13.6% of controls were TGFBR1*6A carriers and TGFBR1*6A was significantly associated with breast cancer (OR 1.48, CI 1.11-1.96). A common variant within the human TGF-beta1 (TGFB1) gene itself is represented by the substitution of Leucine to Proline (T-C) at the 10th amino acid position (T29C). The T-> C substitution results in higher extracellular TGFB1 secretion and higher circulating levels of TGFB1 have been observed in humans who carry the C allele. Investigation of this polymorphism with regard to breast cancer risk has yielded conflicting results. We propose to assess the individual and combined association between these two well-characterized and functionally relevant TGF-beta signaling pathway variants and breast cancer risk using a family-based association study comparing genotypes in 1844 women with breast cancer to those of their 2547 unaffected sisters. We have the following Specific Aims: 1) To assess the association between carrier status of the TGFBR1*6A allele and breast cancer risk. Hypothesis: carrier status of this allele is associated with increased risk of breast cancer. 2) To assess the association between the other functionally relevant variant of the TGF-beta signaling pathway, TGFB1 T29C and breast cancer risk. Hypothesis: carrier status of the T allele is associated with increased risk of breast cancer. 3) To assess the combined effects of TGFBR1 and TGFB1 variants that affect TGF-beta signaling on breast cancer risk. Hypothesis: Individuals with the lowest predicted levels of TGF-beta signaling, i.e. carriers of both the TGFB1 *T allele and the TGFBR1 *6A allele have a increased risk of breast cancer compared to individuals with the lowest predicted levels of TGF-beta signaling, i.e. homozygotes for both the TGFB1*C allele and the TGFBR1*9A allele.