(PQC3) Ethnicity-determined immune response and DCIS outcome

 描述(申请人提供)：乳腺癌(BC)是一种异质性疾病，在BC的不同种族和亚型之间建立了重要的联系。这些因素包括绝经前非裔美国人易患侵袭性三阴性癌症(缺乏ER、PR或HER2表达的肿瘤)。PI(Badve)等人最近的工作表明，量化乳腺癌中的肿瘤浸润性淋巴细胞(TIL)可以预测预后，即使在接受化疗的患者中也是如此。在浸润性癌中，免疫反应是针对肿瘤抗原的，也是由于基质损伤和释放正常隔离的基质抗原，而在导管原位癌中，免疫应答很可能局限于肿瘤抗原。作为对PQ-C3的回应，我们认为免疫反应基因的差异是不同结果的基础，并将决定肿瘤形成早期阶段侵袭性癌症发展的可能性。我们进一步假设，种族差异是免疫反应谱发展的关键决定因素，并可能支持在不同种族乳腺癌患者中观察到的健康差异。与新加坡总医院和牛津大学合作进行的初步研究表明，DCIS病变的免疫特征与级别有关，支持这一假设。为了解决PQC-3，我们将利用祖先档案建立种族注释良好的导管原位癌(DCIS)患者队列(目标1)。我们进一步使用基于多重免疫荧光的新的基于原位分析的多重免疫荧光方法将DCIS中已建立的和新的免疫反应图谱与同侧乳腺事件关联起来，以实现免疫环境的共定位分析(目标2)。同时，我们将执行新的有针对性的深度测序方法，以确定这些民族队列中新的免疫反应谱，并关联同侧浸润性乳腺癌发生的可能性(目标3)。我们的跨国多学科团队装备精良，能够执行必要的任务，并充分表征免疫反应特征以及与乳腺癌早期阶段临床结果的相关性。在这些研究完成后，我们希望确定与DCIS向浸润性癌症进展相关的免疫反应谱，这些免疫反应谱针对每个种族群体。这些免疫图谱与预后的相关性将使我们能够使用这些免疫反应基因来对DCIS患者进行风险分层和疾病进展。这将为减少这些人群中的浸润性乳腺癌奠定基础。

 DESCRIPTION (provided by applicant): Breast cancer (BC) is a heterogeneous disease in which important associations have been established between different ethnic groups and subtypes of BC. These include the predisposition for premenopausal African Americans to develop aggressive triple negative cancers (tumors that lack expression of ER, PR, or HER2). Recent work by the PI (Badve) amongst others shows that quantifying tumor infiltrating lymphocytes (TILs) in breast cancer is prognostic, even in patients treated with chemotherapy. The immune response in invasive carcinoma is directed against tumor antigens as well as due to stromal damage and release of normally sequestered stromal antigens, whereas they are very likely to be restricted to tumor antigens in ductal carcinoma in situ. In response to PQ-C3, we propose that differences in the immune response genes are the basis of disparate outcomes and will determine the likelihood of invasive cancer development in the early stages of tumorigenesis. We further hypothesize that ethnic differences are critical determinants for the development of immune response profiles and could underpin the health disparities observed in different ethnic groups of breast cancer patients. Preliminary studies performed in collaboration with Singapore General Hospital and Oxford University have shown significant differences in the immune profile of DCIS lesions, which are associated with grade, supporting this hypothesis. To address PQC-3, we will develop ethnically well annotated cohorts of ductal carcinoma in situ (DCIS) patients using ancestry profiles (Aim 1).We further correlate established and novel immune response profiles in in "ethnicity annotated" cohorts of DCIS with ipsilateral breast events using novel multiplex immuno- fluorescence based- in situ analytic methods to enable colocalization analysis of the immune milieu (Aim 2). In parallel, we will perform novel targeted deep sequencing methods to identify novel immune response profiles in these ethnic cohorts and correlate the likelihood of ipsilateral invasive breast cancer development (Aim 3). Our multinational multidisciplinary team is well equipped to perform the necessary tasks and fully characterize the immune response profiles and correlation to clinical outcomes in early in early stages of breast cancer. At the completion of these studies, we expect to identify immune response profiles associated with the progression of DCIS to invasive cancer that are specific to the each ethnic group. Correlation of these immune profiles with outcome will enable us to use these immune response genes for risk stratification and disease progression in DCIS patients. This will lay the foundation to reduce invasive breast cancer in these populations.