Biological implications of breast cancer protective variants in Latin American women with high Indigenous American ancestry

具有高美洲原住民血统的拉丁美洲女性乳腺癌保护性变异的生物学意义

• 批准号: 9247151
• 负责人: Laura Fejerman
• 金额: $ 36.26万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9247151
• 关键词: Affect; African American; Alleles; Alternative Splicing; American; Animal Model; Binding; Biological; Biological Assay; Blood specimen; Breast Cancer Patient; California; Cell Proliferation; Cell physiology; Cessation of life; Characteristics; Chromosomes, Human, Pair 6; Clinical Data; Collaborations; Colombian; Development; Disease; ESR1 gene; Epidermal Growth Factor Receptor; Estrogen Receptors; Estrogen receptor negative; Estrogens; Ethnic group; Formalin; Frequencies; GTP-Binding Protein alpha Subunits, Gs; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Genotype; Goals; Histology; Human; In Vitro; Incidence; Indigenous American; Knowledge; Latin American; Latina; Lead; Link; Mammary Neoplasms; Measures; Mexican; National Cancer Institute; North America; Paraffin Embedding; Patients; Peru; Peruvian; Population; Preventive treatment; Progesterone Receptor Status; Progesterone Receptors; Protein Isoforms; Puerto Rican; RNA Sequence Analysis; Receptor Gene; Reporting; Research Personnel; Resources; Risk; S-Phase Fraction; Sample Size; Site; Testing; Time; Tissues; Transcript; Tumor Subtype; Tumor Tissue; Variant; Woman; base; cancer risk; design; experimental analysis; experimental study; genetic variant; genome wide association study; insight; malignant breast neoplasm; protective effect; public health relevance; racial and ethnic; repository; tumor

 DESCRIPTION (provided by applicant): Breast cancer affects 1 in 8 women in the U.S. and is responsible for more than 40,000 deaths per year. Breast cancer risk is not homogeneously distributed among U.S. populations and factors responsible for differences in incidence are not yet understood. Breast cancer incidence in Latinas is 33% lower than in Non- Latina White women. We recently discovered a genetic variant that is only present in populations with Indigenous American ancestry (i.e., genetic ancestry from one of the original groups that populated the American continent before colonization), which provides protection from breast cancer risk. This polymorphism is located near the estrogen receptor 1 gene (ESR1) on chromosome 6, which has been repeatedly implicated in breast cancer. We have conducted preliminary experimental analyses that support the possibility that the genetic variant might be functional. We hypothesize that it influences ESR1 gene expression as well as expression of other genes that depend on the estrogen receptor for transcription. To test this hypothesis, we have established collaboration with the Instituto Nacional de Enfermedades Neoplásicas in Lima, Peru, where investigators have created a large repository of biospecimens, clinical data, tumor histology, treatment, and progression information. We will select biospecimens (formalin fixed paraffin embedded tumor blocks and blood samples) from 2,000 Peruvian women. There are no comparable resources available in the U.S. to study this polymorphism, which is much more common in Peru given the high average Indigenous American ancestry of this population (~80%). In Aim 1 we will examine the association between the Indigenous American genetic variant and tumor subtype, to confirm our original finding of a stronger association with tumors that are negative for the estrogen receptor, and further evaluate the subtype-specific effect, beyond just estrogen receptor characterization. In Aim 2 we will test the association between the variant and expression of the ESR1 gene, as well as expression of other genes that depend on estrogen for expression. In Aim 3, we will test the association between the genetic variant and expression of different versions of ESR1, since we hypothesize that the protective effect of the Indigenous American variant for ER negative disease could be acting through this mechanism. At the conclusion of these studies, we will have expanded our understanding of the mechanisms through which the Indigenous American variant reduces the risk of developing breast cancer and, in particular, the risk of the most aggressive and difficult to treat form of th disease. This project will provide the fundamental knowledge for the design of in-vitro and animal model experiments that could ultimately lead to the development of breast cancer preventive treatment for all women.

 描述（由申请人提供）：乳腺癌影响美国八分之一的女性，每年导致超过 40,000 人死亡。乳腺癌风险在美国人群中分布并不均匀，导致发病率差异的因素尚不清楚。拉丁裔女性的乳腺癌发病率比非拉丁裔白人女性低 33%。我们最近发现了一种仅存在于具有美洲原住民血统的人群（即来自殖民之前居住在美洲大陆的原始群体之一的遗传血统）的遗传变异，它可以提供预防乳腺癌风险的保护。这种多态性位于 6 号染色体上的雌激素受体 1 基因 (ESR1) 附近，该基因已多次与乳腺癌有关。我们进行了初步的实验分析，支持该遗传变异可能具有功能的可能性。我们假设它影响 ESR1 基因表达以及依赖雌激素受体转录的其他基因的表达。为了检验这一假设，我们与秘鲁利马的 Instituto Nacional de Enfermedades Neoplásicas 建立了合作，该研究所的研究人员创建了一个包含生物样本、临床数据、肿瘤组织学、治疗和进展信息的大型存储库。我们将从 2,000 名秘鲁女性中选择生物样本（福尔马林固定石蜡包埋的肿瘤块和血液样本）。美国没有类似的资源来研究这种多态性，考虑到该人群平均有较高的美国原住民血统（~80%），这种多态性在秘鲁更为常见。在目标 1 中，我们将检查美洲原住民遗传变异与肿瘤亚型之间的关联，以证实我们最初的发现，即与雌激素受体阴性的肿瘤有更强的关联，并进一步评估亚型特异性效应，而不仅仅是雌激素受体特征。在目标 2 中，我们将测试 ESR1 基因的变异与表达之间的关联，以及依赖雌激素表达的其他基因的表达。在目标 3 中，我们将测试遗传变异与不同版本的 ESR1 表达之间的关联，因为我们假设美洲原住民变异对 ER 阴性疾病的保护作用可能是通过这种机制发挥作用的。在这些研究结束时，我们将加深对美洲原住民变种降低患乳腺癌风险的机制的理解，特别是降低罹患最具侵袭性和最难治疗的乳腺癌风险的机制。该项目将为体外和动物模型实验的设计提供基础知识，最终可能为所有女性开发乳腺癌预防治疗方法。