TGF-beta polymorphisms and breast cancer in families

TGF-β 多态性与家族乳腺癌

基本信息

批准号：
8134311
负责人：
Boris Pasche
金额：
$ 21.92万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-07 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8134311
关键词：
9q22 ACVR1 gene ACVR1B gene ACVR2 gene ACVR2B gene ACVRL1 gene AMHR2 gene Activins Address Adhesions Affect Alanine Alleles Apoptosis Area BMP10 gene BMP15 gene BMP2 gene BMP3 gene BMP4 BMP5 gene BMP6 gene BMP7 gene BMPR1A gene BMPR2 gene BRCA1 gene BRCA2 gene Bone Morphogenetic Proteins Breast Breast Cancer Cell Case-Control Studies Cell physiology Code Collection Data Diagnostic Neoplasm Staging Dose ERBB2 gene Epidemiologic Studies Epidemiology Epithelial Cells Estrogens Ethnic group Exons Family Frequencies Funding GCG gene GDF10 gene GDF15 gene GDF5 gene GDF8 gene GDF9 gene Gene Expression Genes Genetic Genetic Markers Genetic Polymorphism Genetic Variation Genomics Genotype Growth Growth Factor Haplotypes Hereditary Breast Carcinoma Heterozygote Homozygote Human INHA gene In Vitro Individual Lead Ligands MADH2 gene MADH3 gene MADH4 gene MADH6 gene MADH7 gene Malignant Neoplasms Maps Medical Menopausal Status Messenger RNA Meta-Analysis Morbidity - disease rate Mus Mutation NBL1 gene Names Nodal Outcome Pathogenesis Pathway Analysis Pathway interactions Patients Penetrance Phase Phenotype Population Predisposition Progesterone Prostate Protein Isoforms Proteins Quantitative Trait Loci RNA Receptor Signaling Research Research Personnel Resources Risk SNP genotyping Siblings Signal Pathway Signal Transduction Signaling Pathway Gene Sister Stage at Diagnosis System TGFB1 gene TGFB2 gene TGFB3 gene TGFBR1 gene TGFBR2 gene TGFBR3 gene Testing Transforming Growth Factor beta Triplet Multiple Birth Tumor stage Variant Woman Work base breast cancer family registry breast cancer registry cancer genetics cancer risk case control cell growth cell motility cohort gene function gene interaction genetic epidemiology genetic variant genome wide association study growth differentiation factor 6 growth differentiation factor 7 in vivo insertion/deletion mutation interest lymphoblastoid cell line mRNA Expression malignant breast neoplasm migration mortality mouse model novel protein expression public health relevance receptor tumor

项目摘要

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.

描述（由申请人提供）：生长因子的转化生长因子β（TGF-SS）的超家族性因子调节许多细胞功能，包括细胞生长，粘附，迁移，阳离子的测定和分化以及凋亡。生长因子的TGF-SS超家族的配体包括几种TGF-SS同工型，激活素同工型和骨形态发生蛋白，这些蛋白由不同的基因编码，但通过相似的受体信号传导系统发挥作用。配体，受体蛋白和SMAD细胞内信使的功能对于抑制信号转导至关重要。在这方面，越来越多的证据表明，TGF-SS超家族的配体，受体和细胞内信使的常见变异可能会显着改变乳腺癌的风险和预后。我们是第一个识别TGFBR1*6A的人，这是TGFBR1基因的常见变体。我们对包括6694例乳腺癌病例和8579例对照的14例病例对照研究的荟萃分析表明，与非载体相比，TGFBR1*6A携带者患乳腺癌的风险显着增加。总体而言，TGFBR1*6A纯合子（O.R. 1.40，95％CI 1.04-1.88）的乳腺癌风险高于TGFBR1*6A杂合子（O.R. 1.12，95％CI 1.00-1.25）（Ptrend = 8.41 x 10-4）。 TGFB1基因的一种常见变体与较高的TGF-2水平和TGF-SS分泌增加有关。乳腺癌协会联盟（BCAC）进行的一项最新研究表明，TGFB1 L10P杂合子（O.R. 1.07，95％CI 1.02-1.13）和Holozygotes中的乳腺癌风险增加了。因此，来自同一信号传导途径的一种配体（TGFB1）和一个受体（TGFBR1）编码的天然变体与乳腺癌风险有关。这些结合发现提供了有力的理由，可以全面评估乳腺癌中的TGF-2信号通路。我们建议使用基于家庭的关联研究来评估TGF-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，我们将对5357个姐妹病例和NCI赞助的乳腺癌家庭注册中心的姊妹对照进行全面的基因型分析。与乳腺癌风险相关的遗传变异将使用BCAC的资源进行验证。经过验证的SNP将由BRCA1和BRCA2修饰符的研究人员联盟进一步检查。为了搜索因果变异，我们将1）重新序列验证的200例携带风险单倍型的患者，2）进行密集的SNP基因分型。使用从淋巴细胞细胞系中提取的RNA，我们将独立和共同的功能与功能相关的SNP进行功能表征。在二次分析中，我们将评估各种单倍型和功能相关的乳腺癌风险的关联是否根据肿瘤阶段，ER/PR和ERBB2状态以及更年期状态而有所不同。我们还将确定TGF-2超家族SNP与乳腺癌结果的关联。公共卫生相关性：越来越多的证据表明，TGF-2途径基因的细微变化改变了乳腺癌的风险。该项目将研究5357名乳腺癌女性及其未受影响的姐妹的TGF-2途径的65个基因，并确定哪些基因与乳腺癌风险有关。