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TGF-B signaling pathway, ER-alpha and the heterogeneity of breast cancer risk among Hispanic and non-Hispanic white women.

机译：西班牙裔和非西班牙裔白人女性的TGF-B信号通路，ER-α和乳腺癌风险的异质性。

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摘要

Many risk factors for breast cancer differ between race/ethnic groups. Few studies have included Hispanic women: a genetically admixed population that differs from other ethnic groups for breast cancer incidence, survival, and tumor phenotype. The objective of this study was to determine if genetic variation in ERalpha and TGF-beta signaling genes (TGF-beta1, TGF-betaRI, RUNX1, RUNX2, RUNX3) is associated with breast cancer risk, and if these associations differ between Hispanic and non-Hispanic white women (NHW).;Data from The Breast Cancer Health Disparities (BCHD) study were used. BCHD is a multi-site consortium including two case-control studies within the U.S. and one in Mexico. A total of 3,524 cases (NHW=1,431; Hispanic=2,093) and 4,209 population-based controls (NHW=1,599; Hispanic=2,610) had available DNA. In-person interviews collected information on non-genetic risk factors. Single nucleotide polymorphisms (SNPs) in TGF-beta, RUNX and ERalpha genes were determined using an Illumina platform and PCR. Associations with breast cancer risk were evaluated using multivariable logistic regression, adjusting for study site, age, and Native American genetic ancestry.;Associations with breast cancer phenotypes (ER/PR status) were also evaluated and a genetic risk score (GRS) was calculated to determine the cumulative effect of selected SNPs.;Two SNPs were significantly associated with breast cancer risk: RUNX3 (rs906296 ORCG/GG=1.15 95% CI 1.04-1.26) and TGF-beta1 (rs4803455 ORCA/AA=0.89 95% CI 0.81-0.98). RUNX3 (rs906296) was specifically associated with risk in pre-menopausal women (p=0.002) and in those with moderate to high Native American ancestry. There was a significant interaction between Native American ancestry and RUNX1 (rs7279383, p=0.04). Four RUNX SNPs were associated with an increased risk of ER-/PR- (n=3) and ER-/PR+ (n=1) tumors. A GRS including 6 SNPs (range=0-10 alleles) across ERalpha and TGF-beta signaling genes was positively associated with overall risk (per allele OR=1.14 95% CI 1.04-1.25), as well as ER+, but not ER- tumors.;These results suggest that genetic variation in these genes may explain the greater likelihood in Hispanic women for premenopausal, ER- breast cancer. This is also the first population-based observational study to evaluate crosstalk between TGF-beta and ERalpha signaling pathways. The biological significance of these genes in breast cancer etiology is strongly supported and the results warrant confirmation in future studies.
机译：种族/族裔群体之间的许多乳腺癌危险因素有所不同。很少有研究包括西班牙裔妇女：这是一种遗传混杂的人群，在乳腺癌发生率，生存率和肿瘤表型方面与其他种族不同。这项研究的目的是确定ERalpha和TGF-beta信号基因（TGF-beta1，TGF-betaRI，RUNX1，RUNX2，RUNX3）的遗传变异是否与乳腺癌风险相关，以及西班牙裔和非西班牙裔之间的这些关联是否不同-西班牙裔白人妇女（NHW）；使用了来自乳腺癌健康差异（BCHD）研究的数据。 BCHD是一个多站点的财团，包括美国境内的两项病例对照研究以及墨西哥的一项病例对照研究。共有3,524例（NHW = 1,431;西班牙裔= 2,093）和4,209个基于人群的对照（NHW = 1,599;西班牙裔= 2,610）有可用的DNA。面对面访谈收集了有关非遗传风险因素的信息。使用Illumina平台和PCR确定TGF-beta，RUNX和ERalpha基因中的单核苷酸多态性（SNP）。使用多因素logistic回归评估了乳腺癌风险的相关性，并根据研究地点，年龄和美国原住民的遗传血统进行了调整;还评估了与乳腺癌表型的相关性（ER / PR状态）并计算了遗传风险评分（GRS）来确定所选SNP的累积效应。两个SNP与乳腺癌风险显着相关：RUNX3（rs906296 ORCG / GG = 1.15 95％CI 1.04-1.26）和TGF-beta1（rs4803455 ORCA / AA = 0.89 95％CI 0.81 -0.98）。 RUNX3（rs906296）与绝经前妇女（p = 0.002）和中美洲血统高到美国血统的妇女中的风险特别相关。在美国原住民血统和RUNX1之间存在显着的相互作用（rs7279383，p = 0.04）。四个RUNX SNP与ER- / PR-（n = 3）和ER- / PR +（n = 1）肿瘤的风险增加相关。包含ERalpha和TGF-beta信号基因的6个SNP（范围= 0-10个等位基因）的GRS与总体风险（每个等位基因OR = 1.14 95％CI 1.04-1.25），ER +呈正相关，但与ER-呈正相关这些结果表明，这些基因的遗传变异可能解释了西班牙裔女性绝经前，ER-乳腺癌的可能性更大。这也是评估TGF-β和ERalpha信号通路之间串扰的第一个基于人群的观察性研究。这些基因在乳腺癌病因中的生物学意义得到了强有力的支持，其结果值得在未来的研究中得到证实。

著录项

  • 作者

    Boone, Stephanie Denkhoff.;

  • 作者单位

    University of Louisville.;

  • 授予单位 University of Louisville.;
  • 学科 Health Sciences Epidemiology.;Health Sciences Oncology.;Health Sciences Public Health.
  • 学位 Ph.D.
  • 年度 2013
  • 页码 226 p.
  • 总页数 226
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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