Biological implications of breast cancer protective variants in Latin Americanwomen 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: 10216555
• 负责人: Laura Fejerman
• 金额: $ 50.78万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10216555
• 关键词: Affect; African American; Alleles; Alternative Splicing; American; Animal Model; Binding; Biological; Biological Assay; Biological Specimen Banks; Blood specimen; Breast Cancer Patient; Breast Cancer Risk Factor; California; Cell Proliferation; Cell physiology; Cessation of life; Characteristics; Chromosome 6; Clinical Data; Collaborations; Colombian; Development; Disease; ESR1 gene; Epidermal Growth Factor Receptor; Estrogen Receptors; Estrogen receptor negative; Estrogen receptor positive; 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 allele; protective effect; public health relevance; racial and ethnic; 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（由适用提供）：乳腺癌在美国影响八分之一的妇女，每年造成40,000多人死亡。乳腺癌的风险不是同质分布在美国人群中，而导致事件差异的因素尚未理解。拉丁裔乳腺癌的事件比非拉丁裔白人妇女低33％。我们最近发现了一种遗传变异，仅存在于美国土著血统的种群中（即，来自殖民前美国大陆的原始群体之一的遗传血统），可保护乳腺癌风险。该多态性位于6染色体上的雌激素受体1基因（ESR1）附近，该基因已反复与乳腺癌有关。我们已经进行了初步实验分析，以支持我们假设它影响ESR1基因表达以及其他依赖雌激素受体进行转录的基因的表达的可能性。为了检验这一假设，我们已经与秘鲁利马市的Neoplásicas建立了合作，在那里研究人员创建了大量的生物测量存储库，临床数据，肿瘤组织学，治疗和进展信息。我们将从2,000名秘鲁妇女中选择生物测量（福尔马林）固定石蜡嵌入的肿瘤块和血液样本）。在美国没有可比的资源来研究这种多态性，鉴于该人群的高平均土著血统，在秘鲁，这在秘鲁更为普遍（约80％）。在AIM 1中，我们将检查美国土著遗传变异和肿瘤亚型之间的关联，以确认我们最初发现的与雌激素受体阴性的肿瘤相关性更强的发现，并进一步评估了亚型特异性效应，而不仅仅是雌激素受体受体的表征。在AIM 2中，我们将测试ESR1基因的变体和表达之间的关联，以及依赖雌激素表达的其他基因的表达。在AIM 3中，我们将测试ESR1不同版本的遗传变异和表达之间的关联，因为我们假设本地美国对ER阴性疾病的保护作用可能通过这种机制来起作用。在这些研究结束时，我们将扩展我们对土著美国变种降低乳腺癌的风险，尤其是最具侵略性和最难治疗TH疾病形式的风险的机制的理解。该项目将为设计和动物模型实验的设计提供基本知识，这些实验最终可能导致所有女性的乳腺癌预防治疗。

项目成果

Uncovering Signals of Positive Selection in Peruvian Populations from Three Ecological Regions.

• DOI: 10.1093/molbev/msac158
• 发表时间: 2022-08-03
• 期刊: MOLECULAR BIOLOGY AND EVOLUTION
• 影响因子: 10.7
• 作者: Caro-Consuegra, Rocio;Nieves-Colon, Maria A.;Rawls, Erin;Rubin-de-Celis, Veronica;Lizarraga, Beatriz;Vidaurre, Tatiana;Sandoval, Karla;Fejerman, Laura;Stone, Anne C.;Moreno-Estrada, Andres;Bosch, Elena
• 通讯作者: Bosch, Elena

Breast Cancer Health Disparities in Hispanics/Latinas.

• DOI: 10.1007/s12609-020-00370-3
• 发表时间: 2020-09
• 期刊: Current breast cancer reports
• 影响因子: 0.9
• 作者: Serrano-Gomez SJ;Sanabria-Salas MC;Fejerman L
• 通讯作者: Fejerman L

Breast cancer subtype and survival among Indigenous American women in Peru.

秘鲁美国原住民妇女的乳腺癌亚型和生存率。

• DOI: 10.1371/journal.pone.0201287
• 发表时间: 2018
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Tamayo,LizethI;Vidaurre,Tatiana;NavarroVásquez,Jeannie;Casavilca,Sandro;AramburuPalomino,JessicaI;Calderon,Monica;Abugattas,JulioE;Gomez,HenryL;Castaneda,CarlosA;Song,Sikai;Cherry,Daniel;Rauscher,GarthH;Fejerman,Laura
• 通讯作者: Fejerman,Laura