TGF-beta polymorphisms and breast cancer in families

描述(申请人提供)：转化生长因子-β(TGF-ss)超家族生长因子调节许多细胞功能，包括细胞生长、黏附、迁移、细胞命运决定和分化，以及细胞凋亡。转化生长因子-生长因子超家族的配体包括几种转化生长因子-生长因子亚型、激活素亚型和骨形态发生蛋白，它们由不同的基因编码，但通过相似的受体信号系统发挥作用。配体、受体蛋白和SMAD细胞内信使的功能对抑制信号转导至关重要。在这方面，越来越多的证据表明，转化生长因子-生长因子超家族的配体、受体和细胞内信使的常见变体可能显著改变乳腺癌的风险和预后。我们首次发现了TGFBR1*6A，这是一种常见的TGFBR1基因变异。我们对包括6694例乳腺癌病例和8579例对照在内的14项病例对照研究的荟萃分析表明，与非携带者相比，TGFBR1*6A携带者患乳腺癌的风险显著增加。总体而言，TGFBR1*6A纯合子患乳腺癌的风险(OR值1.40，95%可信区间1.04-1.88)高于TGFBR1*6A杂合子(OR值1.12，95%可信区间1.00-1.25)(P趋势=8.41 x 10-4)。TGFB1基因的一种常见变体与体外循环中较高的转化生长因子-2水平和转化生长因子-ss的分泌增加有关。乳腺癌协会联合会(BCAC)最近进行的一项研究表明，TGFB1 L10P杂合子(O.R.1.07，95%可信区间1.02-1.13)和纯合子(O.R.1.16，95%可信区间1.08-1.25)的乳腺癌风险增加(P趋势=2.8x10-5)。因此，来自同一信号通路的编码一个配体(TGFB1)和一个受体(TGFBR1)的自然发生的变异与乳腺癌的风险有关。这些综合的发现为全面评估乳腺癌中的转化生长因子-2信号通路提供了强有力的理论基础。我们建议使用一项基于家族的关联研究来评估转化生长因子-2超家族65个基因的单倍型与乳腺癌风险之间的关联。总体而言，我们将从NCI赞助的乳腺癌家族登记处对5357例姐妹病例和姐妹对照进行全面的基因分型分析。与乳腺癌风险相关的基因变异将使用BCAC的资源进行验证。BRCA1和BRCA2修饰物调查者联盟将进一步检查经过验证的SNPs。为了寻找因果变异(S)，我们将1)对携带风险单倍型的200名患者的有效区域(S)进行重新排序，2)进行密集的SNP基因分型。利用从淋巴母细胞系中提取的RNA，我们将独立地和联合地对推测的功能相关的SNPs进行功能表征。在二次分析中，我们将评估不同单倍型和功能相关突变与乳腺癌风险的关系是否因肿瘤分期、ER/PR和ERBB2状态以及绝经状态而不同。我们还将确定转化生长因子-2超家族SNPs与乳腺癌预后的关系。 公共卫生相关性： 越来越多的证据表明，转化生长因子-2途径基因的细微变化可以改变乳腺癌的风险。该项目将研究5357名患有乳腺癌的女性及其未受影响的姐妹中的65个转化生长因子-2途径基因，并确定哪些基因与乳腺癌风险相关。

DESCRIPTION (provided by applicant): The Transforming Growth Factor Beta (TGF-ss) superfamily of growth factors regulates many cellular functions including cell growth, adhesion, migration, cell-fate determination and differentiation, and apoptosis. Ligands of the TGF-ss superfamily of growth factors comprises several TGF-ss isoforms, Activin isoforms, and Bone Morphogenetic Proteins, which are encoded by different genes but function through a similar receptor signaling system. The functionality of ligands, receptor proteins and SMAD intracellular messengers is critical for inhibitory signal transduction. There is, in this respect, growing evidence suggesting that common variants of the ligands, receptors and intracellular messengers of the TGF-ss superfamily may significantly modify breast cancer risk and outcome. We were the first to identify TGFBR1*6A, a common variant of the TGFBR1 gene. Our meta-analysis of fourteen case-control studies that included 6694 breast cancer cases and 8579 controls shows that TGFBR1*6A carriers have a significantly increased risk of breast cancer as compared with non- carriers. Overall, breast cancer risk is higher among TGFBR1*6A homozygotes (O.R. 1.40, 95% CI 1.04-1.88) than among TGFBR1*6A heterozygotes (O.R. 1.12, 95% CI 1.00-1.25) (Ptrend =8.41 x 10-4). A common variant of the TGFB1 gene has been associated with higher circulating levels of TGF-2 and increased TGF-ss secretion in vitro. A recent study conducted by the Breast Cancer Association Consortium (BCAC) has shown that breast cancer risk was increased among TGFB1 L10P heterozygotes (O.R. 1.07, 95% CI 1.02-1.13) and homozygotes (O.R. 1.16, 95% CI 1.08-1.25) (Ptrend = 2.8 x 10-5). Hence, naturally-occurring variants encoding for one ligand (TGFB1) and one receptor (TGFBR1) from the same signaling pathway are associated with breast cancer risk. These combined findings provide a strong rationale to comprehensively assess the TGF-2 signaling pathway in breast cancer. We propose to assess the association between haplotypes of the 65 genes of the TGF-2 superfamily and breast cancer risk using a family-based association study. Overall, we will perform a comprehensive genotypic analysis of the pathway in 5357 sister cases and sister controls from the NCI-sponsored Breast Cancer Family Registry. Genetic variants associated with breast cancer risk will be validated using the resources of BCAC. Validated SNPs will be further examined by the Consortium of Investigators of Modifiers of BRCA1 and BRCA2. To search for the causal variant(s) we will 1) re-sequence the validated region(s) in 200 patients that carry the risk haplotypes, 2) perform dense SNP genotyping. Using RNA extracted from lymphoblastoid cell lines we will functionally characterize the putative functionally-relevant SNPs independently and jointly. In secondary analyses, we will evaluate whether the associations of the various haplotypes and functionally-relevant mutations with breast cancer risk differ according to tumor stage, ER/PR and ERBB2 status and menopausal status. We will also determine the association of the TGF-2 superfamily SNPs with breast cancer outcomes. PUBLIC HEALTH RELEVANCE: There is growing evidence that subtle changes in genes of the TGF-2 pathway modify breast cancer risk. This project will study 65 genes of the TGF-2 pathway in 5357 women with breast cancer and their unaffected sisters and determine which genes are associated with breast cancer risk.