The DARC side of Breast Cancer Disparities - African Ancestry and Cancer- Related Immune Response

DARC 方面乳腺癌差异 - 非洲血统和癌症相关免疫反应

• 批准号: 10198536
• 负责人: Melissa B Davis
• 金额: $ 51.74万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-23 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10198536
• 关键词: 3-Dimensional; Affect; Africa; African; African American; African Caribbean; Age; Alleles; Anthropology; Area; Automobile Driving; Biodiversity; Biology; Breast Cancer Patient; Breast Cancer Treatment; Caribbean region; Cells; Characteristics; Clinical; Country; Coupled; Cytometry; DNA; Data; Data Set; Diabetes Mellitus; Diagnosis; Disease; Epithelial; Ethiopia; Etiology; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Risk; Genetic Variation; Genomics; Ghana; Healthcare; Heterogeneity; High Prevalence; Immune; Immune response; Immunologics; Immunotherapy; In Situ; Incidence; Individual; Infiltration; Inflammation; Inflammatory; Investigation; Kenya; Latinx; Leukocytes; Link; Malignant Neoplasms; Mammary Neoplasms; Modeling; Myelogenous; Nigeria; Obesity; Organoids; Outcome; Pathologic; Pathologist; Pathology; Pathway interactions; Patient Self-Report; Patients; Pattern; Phenotype; Population; Population Genetics; Population Heterogeneity; Primary Neoplasm; Privatization; Proteins; Proteomics; Race; Regulation; Reporting; Risk; Side; Stage at Diagnosis; Surgical Oncologist; Survival Rate; Tissue-Specific Gene Expression; Tumor Biology; Tumor Subtype; Tumor-infiltrating immune cells; Variant; Woman; Work; base; cancer genome; cancer health disparity; cancer subtypes; caucasian American; cell behavior; cell type; cohort; comorbidity; genetic variant; genome sequencing; health disparity; improved; inflammatory marker; innovation; insight; malignant breast neoplasm; mortality; mortality disparity; multi-ethnic; multidisciplinary; multiple omics; multiplexed imaging; neoplastic cell; novel; patient stratification; personalized care; population based; prognostic; prospective; recruit; response; targeted treatment; transcriptome; transcriptome sequencing; translational study; treatment response; triple-negative invasive breast carcinoma; tumor; tumor heterogeneity; tumor microenvironment; tumor-immune system interactions; whole genome

PROJECT SUMMARY (tech abs) Even with the typical delays in diagnosis, more advanced stage distribution at diagnosis, and inadequate multidisciplinary breast cancer treatment, these combined factors do not completely explain disparities in breast cancer mortality outcomes, which persist after controlling for stage at diagnosis – and have been so for the past 50 years. The approximately two-fold increased risk of TNBC in AA women has been confirmed by population-based incidence rates regionally as well as nationally and across all age intervals. Compared to non-TNBC, triple negative disease has been confirmed to be an adverse prognostic feature in AA patients, driving some of the mortality disparities. We hypothesize that altered mechanisms of tumor immune responses, which underlies TNBC tumor biology differences between SRR, are caused by population-private genetic variants among individuals with shared west African ancestry. These evolutionarily selected variants alter immune cell behavior and inflammatory mechanisms, leading to novel tumor-immune cell types and significant differences in leukocyte infiltration patterns, which may be associated with poor outcomes. We will perform an innovative multiomics investigation of African-specific gene expression in TNBC, linked to immunological tumor phenotypes. We will harness the novelty of rarely-investigated breast cancer patient populations from diverse African regions with TNBC cases from g admixed populations (i.e. African-American and Afro-Caribbean). The most impactful innovation of this study is the characterization of differential gene expression, coupled with integrated proteomics data, to identify novel tumor phenotypes that are shared among women of the African diaspora. This work will be transformative to our understanding of tumor heterogeneity and biological diversity across patient groups. We propose the follow aims: 1- Determine the ancestry- associated differential gene expression profiles of immune and inflammatory-related genes in primary tumors across an African-enriched cohort of 400 clinically annotated TNBC cases, to immune profiles linked to shared west African genetic ancestry. 2- Characterize ancestry-associated differences in pathological tumor immune response characteristics, including differences in tumor inflammation and/or tumor infiltration of specific immune cell types. 3-Create an African-enriched panel of ex vivo models to validate/investigate the ancestry-associated drivers of altered genetic pathways and immune responses. By completing these aims we expect to yield an African-enriched set of population-private, validated eQTLs, associated with TNBC immune response mechanisms that can be further interrogated by our authenticated ex vivo models.

项目摘要（Tech ABS） 即使在诊断方面的典型延迟，诊断性的更高级舞台分布以及多学科的不足 乳腺癌治疗，这些综合因素不能完全解释乳腺癌死亡率的差异， 在控制诊断阶段之后，它一直持续存在 - 在过去的50年中一直如此。大约两个倍 AA妇女中TNBC的风险增加已得到区域性基于人群的事件率以及 全国和所有年龄间隔。与非TNBC相比，三重阴性疾病已被证实为逆境 AA患者的预后特征，驱动了一些死亡率差异。我们假设改变的机制 SRR之间TNBC肿瘤生物学差异的基础的肿瘤免疫反应是由种群私有的 具有共同西非血统的个体的遗传变异。这些进化选择的变体改变了免疫 细胞行为和炎症机制，导致新型肿瘤免疫细胞类型，并在 白细胞浸润模式，可能与差的结果有关。我们将执行创新的多组学 对TNBC中非洲特异性基因表达的研究，与免疫肿瘤表型有关。我们会利用的 来自非洲潜水区的乳腺癌患者种群很少有TNBC病例的新颖性 混合人口（即非裔美国人和非洲加勒比海）。这项研究最有影响力的创新是 差异基因表达的表征，再加上整合的蛋白质组学数据，以鉴定新型肿瘤表型 在非洲侨民的妇女中共享。这项工作将是我们对肿瘤的理解的影响 患者群体之间的异质性和生物多样性。我们提出以下目的：1-确定祖先 - 跨个性肿瘤中免疫和炎症相关基因的相关差异基因表达谱。 非洲富含400个临床注释的TNBC病例的队列，与与共享西非通用的免疫学概况 祖先。 2-表征与祖先相关的病理肿瘤免疫增强特征的差异，包括 特定免疫细胞类型的肿瘤注射和/或肿瘤注射的差异。 3创建非洲富含的 离体模型的面板验证/研究遗传途径改变的祖先相关驱动因素和免疫 回答。通过完成这些目标，我们预计将产生一套富含非洲的人群私人，经过验证的EQTL， 与我们身份验证的离体模型可以进一步询问的TNBC免疫反应机制相关。