(PQC3) Ethnicity-determined immune response and DCIS outcome

(PQC3) 种族决定的免疫反应和 DCIS 结果

基本信息

批准号：
9123566
负责人：
Sunil S. Badve
金额：
$ 68.5万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-04 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9123566
关键词：
Address Adverse effects Adverse event African African American Antigens Asians B-Lymphocytes Biological Assay Breast Breast Cancer Patient Cancer Center Carcinoma Cells Clinical Collaborations Data Development Disease Disease Progression ERBB2 gene Epithelial Estrogen Receptors Ethnic Origin Ethnic group European Event Fluorescence Foundations Gene Mutation General Hospitals Genes Genetic Health Hispanics Immune Immune Response Genes Immune response Immune system Immunofluorescence Immunologic Immunologic Markers In Situ In Situ Lesion Incidence Indiana Ipsilateral Knowledge Lesion Malignant Neoplasms Mammography Measurement Methods Molecular Mutation Natural Killer Cells Noninfiltrating Intraductal Carcinoma Normal tissue morphology Operative Surgical Procedures Outcome Patient-Focused Outcomes Patients Pattern Plasma Cells Population Predisposition Premenopause Progesterone Receptors RNA Splicing Race Radiation Radiation therapy Recurrence Regimen Risk Role Singapore Staging Stratification Tumor Antigens Tumor-Infiltrating Lymphocytes Universities Variant Woman Work base cancer health disparity cancer prevention chemotherapy cohort combinatorial deep sequencing design differential expression ethnic difference follow-up genetic profiling health disparity hormone therapy macrophage malignant breast neoplasm multidisciplinary novel novel strategies outcome forecast prevent prognostic protein biomarkers racial and ethnic racial difference receptor expression response skills standard of care tool transcriptome sequencing tumor tumor immunology tumorigenesis

项目摘要

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.

描述（由应用提供）：乳腺癌（BC）是一种异质疾病，在不同种族和卑诗省的亚型之间已经建立了重要的关联。其中包括绝经前非洲裔美国人开发侵略性三重阴性癌（缺乏ER，PR或HER2表达的肿瘤）的倾向。 PI（Badve）等人最近的工作表明，即使在接受化学疗法治疗的患者中，量化乳腺癌中肿瘤浸润淋巴细胞（TIL）也是预后的。浸润性癌中的免疫反应针对肿瘤抗原，以及基质损伤和正常隔离的基质抗原的释放引起的，而它们很可能仅限于当地导管癌中的肿瘤抗原。为了响应PQ-C3，我们建议免疫增强基因的差异是不同结果的基础，并将决定肿瘤发生早期侵入性癌症发展的可能性。我们进一步假设，种族差异是免疫增强特征发展的关键决定者，并且可以支持在不同种族的乳腺癌患者中观察到的健康分布。与新加坡综合医院和牛津大学合作进行的初步研究表明，DCIS病变的免疫响应概况有显着差异，与等级有关，支持这一假设。为了解决PQC-3，我们将使用祖先特征开发出良好的注释导管癌的同类（DCIS）患者（AIM 1）。我们进一步将建立的和新颖的免疫响应特征与“种族相关”中的“种族相关”中的dcis中的同伴分析的繁殖率分析，从免疫环境（目标2）。同时，我们将执行新颖的有针对性的深层测序方法，以鉴定这些族裔队列中新型的免疫响应特征，并将同侧浸润性乳腺癌发育的可能性相关联（AIM 3）。我们的跨国跨学科团队能够完成必要的任务，并在乳腺癌初期早期的临床结果充分表征与临床结局的相关性。这些研究完成后，我们希望确定与DCIS在每个种族中特有的侵入性癌症相关的免疫传感器谱。这些免疫响应特征与结果的相关性将使我们能够使用这些免疫响应基因进行DCIS患者的风险分层和疾病进展。这将奠定基础，以减少这些人群的侵入性乳腺癌。