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

项目摘要(技术简介) 即使有典型的诊断延迟，诊断时更高级的阶段分布，以及不充分的多学科 乳腺癌治疗，这些综合因素并不能完全解释乳腺癌死亡率结果的差异， 在诊断时控制了分期后，这种情况仍然存在--在过去的50年里一直如此。大约两倍于 再生障碍性贫血妇女患TNBC的风险增加已被基于人群的发病率以及 在全国范围内和所有年龄段。与非TNBC相比，三阴性疾病已被证实是一种不良反应 再生障碍性贫血患者的预后特征，导致了一些死亡率差异。我们假设，改变的机制 肿瘤免疫反应是由群体特异性引起的，它是TNBC和SRR肿瘤生物学差异的基础 具有共同西非血统的个体之间的基因变异。这些进化选择的变体改变了免疫力 细胞行为和炎症机制，导致新的肿瘤免疫细胞类型和显著差异 白细胞渗入模式，这可能与不良预后有关。我们将进行创新的多元经济学 研究非洲特异性基因在TNBC中的表达，与免疫学肿瘤表型有关。我们会驾驭 非洲不同地区很少调查的乳腺癌患者群体的新颖性 混杂人口(即非洲裔美国人和非洲裔加勒比人)。这项研究最有影响力的创新是 鉴定差异基因表达，结合综合蛋白质组学数据，以识别新的肿瘤表型 在散居海外的非洲妇女中分享的。这项工作将改变我们对肿瘤的理解 患者群体的异质性和生物多样性。我们提出了以下目标：1-确定祖先- 免疫和炎症相关基因在不同地区原发肿瘤中的差异表达 400例临床标注的TNBC病例的非洲浓缩队列，与与共享的西非基因有关的免疫图谱 血统。2-表征与祖先相关的病理肿瘤免疫反应特征的差异，包括 肿瘤炎症和/或肿瘤特定免疫细胞类型的浸润性差异。3-创建一个富含非洲人的 验证/研究遗传途径和免疫改变的祖先相关驱动因素的体外模型小组 回应。通过实现这些目标，我们预计将产生一套非洲丰富的人口私有、有效的eQTL， 与TNBC免疫反应机制相关，可以通过我们认证的体外模型进一步研究。

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.