TGF-beta pathway variants and breast cancer in families

描述（由申请人提供）：我们是第一个鉴定TGFBR 1 *6A的人，TGFBR 1基因的一种常见变体（编码I型TGF-β受体）。我们已经表明，TGF-β受体1 *6A传递TGF-β生长抑制信号的效率明显低于TGF-β受体1。在对已发表的三项关于TGFBR 1 *6A和乳腺癌的病例对照研究（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%的对照为TGFBR 1 *6A携带者，TGFBR 1 *6A与乳腺癌显著相关（OR 1.48，CI 1.11-1.96）。人TGF-β 1（TGFB 1）基因本身的一种常见变体是在第10个氨基酸位置（T29 C）由亮氨酸取代为脯氨酸（T-C）。T-> C取代导致细胞外TGFB 1分泌增加，并且在携带C等位基因的人类中观察到TGFB 1循环水平升高。对这种多态性与乳腺癌风险的研究产生了相互矛盾的结果。我们建议评估这两种特征良好且功能相关的TGF-β信号通路变异体与乳腺癌风险之间的个体和组合关联，使用基于家庭的关联研究，比较1844名乳腺癌女性与2547名未受影响的姐妹篇的基因型。我们有以下具体目标： 1)评估TGFBR 1 *6A等位基因携带状态与乳腺癌风险之间的关系。假设：该等位基因的携带状态与乳腺癌风险增加相关。2)评估TGF-β信号通路的其他功能相关变体TGFB 1 T29 C与乳腺癌风险之间的关联。假设：T等位基因携带状态与乳腺癌风险增加相关。 3)评估TGFBR 1和TGFB 1变体对乳腺癌风险的影响。假设：与具有最低预测TGF-β信号传导水平的个体（即TGFB 1 *C等位基因和TGFBR 1 *9A等位基因的纯合子）相比，具有最低预测TGF-β信号传导水平的个体（即TGFB 1 *T等位基因和TGFBR 1 *6A等位基因的携带者）具有增加的乳腺癌风险。

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.