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）超家族调节许多细胞功能，包括细胞生长、粘附、迁移、细胞命运决定和分化以及细胞凋亡。生长因子 TGF-β 超家族的配体包括多种 TGF-β 同工型、激活素同工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-β超家族的配体、受体和细胞内信使的常见变体可能会显着改变乳腺癌的风险和结果。我们是第一个发现 TGFBR1*6A（TGFBR1 基因的常见变体）的人。我们对 14 项病例对照研究（包括 6694 例乳腺癌病例和 8579 例对照）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着增加。总体而言，TGFBR1*6A 纯合子（O.R. 1.40，95% CI 1.04-1.88）患乳腺癌的风险高于 TGFBR1*6A 杂合子（O.R. 1.12，95% CI 1.00-1.25）（Ptrend =8.41 x 10-4）。 TGFB1 基因的一个常见变体与较高的 TGF-2 循环水平和体外 TGF-β 分泌增加有关。乳腺癌协会联盟 (BCAC) 最近进行的一项研究表明，TGFB1 L10P 杂合子（O.R. 1.07，95% CI 1.02-1.13）和纯合子（O.R. 1.16，95% CI 1.08-1.25）患乳腺癌的风险增加（ P 趋势 = 2.8 x 10-5)。因此，编码来自同一信号通路的一种配体 (TGFB1) 和一种受体 (TGFBR1) 的天然变异体与乳腺癌风险相关。这些综合发现为全面评估乳腺癌中的 TGF-2 信号通路提供了强有力的依据。我们建议使用基于家族的关联研究来评估 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，我们将对来自 NCI 赞助的乳腺癌家族登记处的 5357 例姐妹病例和姐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利用 BCAC 的资源进行验证。 BRCA1 和 BRCA2 修饰物研究人员联盟将进一步检查经过验证的 SNP。为了寻找因果变异，我们将 1) 对 200 名携带风险单倍型的患者的验证区域进行重新测序，2) 进行密集 SNP 基因分型。使用从类淋巴母细胞系中提取的 RNA，我们将独立和联合地对假定的功能相关 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突变与乳腺癌风险的关联是否因肿瘤分期、ER/PR 和 ERBB2 状态以及绝经状态而异。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 通路基因的细微变化会改变乳腺癌风险。该项目将研究 5357 名乳腺癌女性及其未患病姐妹的 TGF-2 通路的 65 个基因，并确定哪些基因与乳腺癌风险相关。