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: 10209573
• 负责人: PETER KRAFT
• 金额: $ 76.46万
• 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/10209573
• 关键词: Address; African; African American; Area; Bioinformatics; Biology; Breast Cancer Epidemiology; Breast Cancer Patient; Breast Cancer Risk Factor; Cancer Prevention Study II; Cessation of life; Characteristics; Clinical; DNA; Data; Databases; Diagnostic; Epidemiology; Etiology; European; Evolution; Frequencies; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Variation; Genomics; Immune; Immune response; Immunooncology; Immunotherapy; Joints; Knowledge; Light; 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 prevention; cancer subtypes; chemotherapy; cohort; disorder prevention; epidemiology study; exome sequencing; experience; genetic association; 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.

三重阴性乳腺癌（TNBC）通常是侵略性癌症，中位时间较短 死亡比其他乳腺癌。由于这些癌症是通过缺乏目标来定义的，所以识别 量身定制的疗法受到了挑战。但是，免疫疗法在TNBC中显示出重要的希望， 包括首次获得乳腺癌免疫疗法的FDA批准和有利的反应数据 将免疫疗法添加到新辅助化学疗法中。最近的证据表明肿瘤分子 特征可以为TNBC的不同病因和预后提供线索。基因表达 研究表明，TNBC是异质的，由更细的亚型组成，部分由免疫定义 响应签名。已经假设患者的免疫反应在 确定肿瘤进展。此外，测序研究已经确定了一组经常是 在乳腺肿瘤和几个反映不同诱变过程的突变特征中突变，并且可能 具有病因。在TNBC中鉴定的突变特征与 更常见的腔乳腺癌，强调了对该亚型的研究的需求。 我们建议对匹配的肿瘤和种系DNA样品进行整个外显子组测序（WES） 护士健康研究护士健康研究的400名TNBC患者来自400名TNBC患者 II，癌症预防研究II和癌症预防研究3。 种系GWA，乳腺癌危险因素和肿瘤免疫特征，我们的位置很好 了解遗传和非遗传危险因素如何影响乳腺肿瘤突变特征，免疫 反应和预后。我们将评估遗传和非遗传风险因素与肿瘤的关联 突变特征（AIM 1）和肿瘤免疫特征（AIM 2）。我们还将检查 免疫反应特征和肿瘤突变谱（AIM 3）。在探索性分析中，我们将评估 躯体突变特征和免疫反应特征的可能关节作用是 与乳腺癌特异性生存有关（AIM 4）。这项研究的知识将非常有价值 为这些侵略性肿瘤制定预防策略和治疗目标。 为了完成这些目标，我们组建了一个跨学科的乳腺癌专家团队 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。主要调查人员在队列资源方面拥有丰富的经验，并且已经工作了 合作十多年。我们还与B-Cast和Amber Consortia合作 创建来自TNBC的WES数据的庞大而多样的存储库，这将使我们既能复制我们的 结果并比较突变曲线及其与诊断和临床因素的关联 欧洲人和非洲裔美国妇女。