Prediagnostic exposures, germline genetics, and triple negative breast cancer mutational and immune profiles

诊断前暴露、种系遗传学以及三阴性乳腺癌突变和免疫特征

• 批准号: 10596120
• 负责人: Rulla M Tamimi
• 金额: $ 46.16万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10596120
• 关键词: Address; Adjuvant Chemotherapy; African American; African ancestry; Area; Bioinformatics; Biology; Breast Cancer Epidemiology; Breast Cancer Patient; Breast Cancer Risk Factor; Cancer Prevention Study II; Categories; Cessation of life; Characteristics; Clinical; DNA; Data; Databases; Diagnostic; Disease; Epidemiology; Etiology; European ancestry; Evolution; Frequencies; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Variation; Genomics; Immune; Immune response; Immunooncology; Immunotherapy; Joints; Knowledge; Link; Malignant Neoplasms; Mammary Neoplasms; Molecular; Molecular Biology; Mutate; Mutation; Neoadjuvant Therapy; Nurses' Health Study; Pathologic Mutagenesis; Pathology; Patients; Play; Positioning Attribute; Prevention; Prevention strategy; Principal Investigator; Prognosis; Prospective, cohort study; Relapse; Research; Resources; Risk; Risk Factors; Role; Sampling; Somatic Mutation; The Cancer Genome Atlas; Time; Tissues; Woman; Work; cancer subtypes; cohort; epidemiology study; exome sequencing; experience; genetic epidemiology; genome wide association study; genome-wide; individualized medicine; interest; malignant breast neoplasm; molecular subtypes; multidisciplinary; non-genetic; phenotypic data; prospective; repository; response; treatment response; triple-negative invasive breast carcinoma; tumor; tumor exome; tumor progression

Triple negative breast cancer (TNBC) are typically aggressive cancers with shorter median time to relapse and death than other breast cancers. Because these cancers are defined by the absence of a target, identification of tailored therapies has been challenging. However, immune therapy shows important promise in TNBC, including the first FDA approval for immunotherapy in breast cancer and favorable response data for the addition of immunotherapy to neoadjuvant chemotherapy. Recent evidence suggests that tumor molecular characteristics may provide clues to both the different etiology and prognoses for TNBCs. Gene expression studies revealed that TNBCs are heterogeneous and composed of finer subtypes, defined in part by immune response signatures. It has been hypothesized that the patients’ immune response plays an important role in determining tumor progression. Further, sequencing studies have identified a set of genes that are frequently mutated in breast tumors and several mutational signatures that reflect distinct mutagenic processes, and may have etiologic implications. The mutational signatures that have been identified in TNBCs are distinct from the more common luminal breast cancers, highlighting the need for research specific to this subtype. We propose to perform whole exome sequencing (WES) of matched tumor and germline DNA samples from 400 TNBC patients from four prospective cohort studies, the Nurses’ Health Study, Nurses’ Health Study II, Cancer Prevention Study II, and Cancer Prevention Study 3. In combination with our existing rich database of germline GWAS, breast cancer risk factors, and tumor immune signatures, we are well positioned to better understand how genetic and nongenetic risk factors influence breast tumor mutational signatures, immune response and prognosis. We will assess the association of genetic and nongenetic risk factors with tumor mutational profiles (Aim 1), and tumor immune profiles (Aim 2). We will also examine the association between immune response signatures and tumor mutation profiles (Aim 3). In exploratory analyses, we will evaluate whether a possible joint effect of somatic mutational signatures and immune response signatures are associated with breast cancer-specific survival (Aim 4). Knowledge from this study will be extremely valuable in developing prevention strategies and treatment targets for these aggressive tumors. To complete these aims, we have assembled a multidisciplinary team of experts in breast cancer epidemiology, genetic epidemiology, statistical genetics, bioinformatics, immuno-oncology, and tumor genomics. The Principal Investigators have extensive experience with the cohort resources and have worked collaboratively for over thirteen years. We have also partnered with the B-CAST and AMBER consortia to create a large and diverse repository of WES data from TNBCs, which will enable us to both replicate our results and compare mutational profiles and their associations with prediagnostic and clinical factors in European-ancestry and African American women.

三阴性乳腺癌（TNBC）通常是侵袭性癌症，中位复发时间较短，并且 因为这些癌症的定义是缺乏靶标、识别。 然而，免疫疗法在 TNBC 中显示出重要的前景。 包括 FDA 首次批准乳腺癌免疫疗法以及良好的反应数据 最近的证据表明，在新辅助化疗中添加免疫疗法。 这些特征可能为 TNBC 基因表达的不同病因和预后提供线索。 研究表明，TNBC 具有异质性，由更精细的亚型组成，部分由免疫系统定义 众所周知，患者的免疫反应在其中发挥着重要作用。 此外，测序研究还确定了一组经常出现的基因。 在乳腺肿瘤中发生突变，并且一些突变特征反映了不同的诱变过程，并且可能 TNBC 中已确定的突变特征与 TNBC 不同。 更常见的管腔乳腺癌，强调了针对这种亚型进行研究的必要性。 我们建议对匹配的肿瘤和种系 DNA 样本进行全外显子组测序 (WES) 来自四项前瞻性队列研究（护士健康研究、护士健康研究）的 400 名 TNBC 患者 II、癌症预防研究II、癌症预防研究3。结合我们现有丰富的数据库 种系 GWAS、乳腺癌危险因素和肿瘤免疫特征，我们有能力更好地 了解遗传和非遗传风险因素如何影响乳腺肿瘤突变特征、免疫 我们将评估遗传和非遗传危险因素与肿瘤的关联。 我们还将检查突变谱（目标 1）和肿瘤免疫谱（目标 2）之间的关联。 在探索性分析中，我们将评估免疫反应特征和肿瘤突变谱（目标 3）。 体细胞突变特征和免疫反应特征是否可能存在联合效应 与乳腺癌特异性生存相关（目标 4）。 制定这些侵袭性肿瘤的预防策略和治疗目标。 为了实现这些目标，我们组建了一支乳腺癌多学科专家团队 流行病学、遗传流行病学、统计遗传学、生物信息学、免疫肿瘤学和肿瘤 基因组学的主要研究人员在队列资源方面拥有丰富的经验，并且已经开展了工作。 我们还与 B-CAST 和 AMBER 联盟合作超过 13 年。 创建一个来自 TNBC 的大型且多样化的 WES 数据存储库，这将使我们能够复制我们的 结果并比较突变谱及其与诊断前和临床因素的关联 欧洲血统和非裔美国女性。