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: 9768900
• 负责人: Laura Fejerman
• 金额: $ 35.17万
• 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 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9768900
• 关键词: Affect; African American; Alleles; Alternative Splicing; American; Animal Model; Binding; Biological; Biological Assay; Blood specimen; Breast Cancer Patient; Breast Cancer Risk Factor; 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; 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; design; experimental analysis; experimental study; genetic variant; genome wide association study; in vitro Model; 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妇女，每年造成超过40，000人死亡。乳腺癌风险在美国人群中分布不均匀，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色女性低33%。我们最近发现了一种遗传变异，这种变异只存在于具有美洲原住民血统的人群中（即，遗传祖先来自殖民前居住在美洲大陆的原始群体之一），这提供了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（ESR 1）附近，该基因多次与乳腺癌有关。我们已经进行了初步的实验分析，支持遗传变异可能是功能性的。我们假设它影响ESR 1基因的表达以及其他依赖于雌激素受体转录的基因的表达。为了验证这一假设，我们与位于秘鲁利马的国家肿瘤研究所建立了合作关系，研究人员在那里建立了一个大型的生物标本、临床数据、肿瘤组织学、治疗和进展信息库。我们将从2,000名秘鲁妇女中选择生物标本（福尔马林固定石蜡包埋的肿瘤块和血液样本）。在美国没有可比较的资源来研究这种多态性，考虑到这一人群的平均美洲土著血统（约80%），这种多态性在秘鲁更为常见。在目标1中，我们将研究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表征。在目标2中，我们将测试ESR 1基因的变体和表达之间的关联，以及依赖于雌激素表达的其他基因的表达。在目标3中，我们将测试ESR 1的不同版本的遗传变异和表达之间的关联，因为我们假设美洲土著变异对ER阴性疾病的保护作用可能是通过这种机制起作用的。在这些研究的结论中，我们将扩大我们对美洲原住民变体降低患乳腺癌风险的机制的理解，特别是最具侵略性和最难治疗的疾病形式的风险。该项目将为体外和动物模型实验的设计提供基础知识，最终可能导致为所有妇女开发乳腺癌预防性治疗。