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

项目概要（tech abs） 即使有典型的诊断延迟，诊断时更先进的阶段分布，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， 在控制了诊断时的分期后，这种情况仍然存在--而且在过去的50年里一直如此。大约两倍的 AA女性TNBC风险增加已被区域人群发病率以及 在全国范围内，在所有年龄段。与非TNBC相比，三阴性疾病已被证实是一种不利的疾病。 AA患者的预后特征，导致一些死亡率差异。我们假设， 肿瘤免疫应答是SRR之间TNBC肿瘤生物学差异的基础，是由人群特异性免疫应答引起的。 有共同西非血统的个体之间的遗传变异。这些进化选择的变异改变了免疫系统。 细胞行为和炎症机制，导致新的肿瘤免疫细胞类型和显着差异， 白细胞浸润模式，这可能与不良结局相关。我们将进行创新的多组学 TNBC中非洲特异性基因表达的研究，与免疫肿瘤表型相关。我们将利用 来自不同非洲地区的TNBC病例很少调查的乳腺癌患者人群的新奇， 混合人群（即非洲裔美国人和非洲裔加勒比人）。本研究最具影响力的创新是 差异基因表达的表征，结合整合的蛋白质组学数据，以识别新的肿瘤表型 这些都是非洲妇女的共同点。这项工作将改变我们对肿瘤的理解 异质性和生物多样性。我们提出以下目标：1-确定祖先- 免疫和炎症相关基因在原发性肿瘤中的相关差异基因表达谱， 400例临床注释的TNBC病例的非洲富集队列，与共享的西非遗传相关的免疫特征 祖先2-描述与祖先相关的病理肿瘤免疫反应特征差异，包括 肿瘤炎症和/或特定免疫细胞类型的肿瘤浸润的差异。3-创造一个非洲丰富的 一组离体模型，用于验证/研究改变遗传途径和免疫的祖先相关驱动因素 应答通过完成这些目标，我们期望产生一组非洲丰富的群体私有的、经验证的eQTL， 与TNBC免疫应答机制相关，可以通过我们验证的离体模型进一步询问。

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.