(PQC3) Ethnicity-determined immune response and DCIS outcome

 描述（由申请人提供）：乳腺癌（BC）是一种异质性疾病，在不同种族和BC亚型之间已建立了重要的关联。这些包括绝经前非洲裔美国人发展侵袭性三阴性癌症（缺乏ER，PR或HER 2表达的肿瘤）的倾向。PI（Badve）的最新研究表明，即使在接受化疗的患者中，量化乳腺癌中的肿瘤浸润淋巴细胞（TIL）也具有预后意义。侵袭性癌中的免疫反应是针对肿瘤抗原的，也是由于基质损伤和正常隔离的基质抗原的释放，而它们很可能仅限于原位导管癌中的肿瘤抗原。针对PQ-C3，我们提出免疫应答基因的差异是不同结果的基础，并将决定肿瘤发生早期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显示，DCIS病变的免疫特征存在显著差异，与分级相关，支持这一假设。 为了解决PQC-3，我们将使用祖先特征来开发具有良好种族注释的导管原位癌（DCIS）患者的队列（目标1）。我们进一步使用基于新型多重免疫荧光的原位分析方法将“具有种族注释”的DCIS队列中已建立的和新型的免疫应答特征与同侧乳腺事件相关联，以实现免疫环境的共定位分析（目标2）。与此同时，我们将进行新的靶向深度测序方法，以确定这些种族队列中的新免疫应答谱，并与同侧浸润性乳腺癌发展的可能性相关联（目标3）。我们的多国多学科团队配备精良，能够执行必要的任务，并充分表征乳腺癌早期阶段的免疫反应特征及其与临床结局的相关性。 在这些研究完成后，我们希望确定与DCIS进展为浸润性癌症相关的免疫反应谱，这些免疫反应谱对每个种族群体都是特异性的。这些免疫特征与结果的相关性将使我们能够使用这些免疫应答基因进行DCIS患者的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.