Evolution and clinical impact of clonal hematopoiesis of indeterminate potential in breast tumor microenvironment

乳腺肿瘤微环境中不确定潜力克隆造血的进化和临床影响

• 批准号: 10610871
• 负责人: Shridar Ganesan
• 金额: $ 63.01万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10610871
• 关键词: Acceleration; Acute; Adjuvant; Adverse event; Aftercare; Age; Architecture; Biological Assay; Biopsy Specimen; Blood specimen; Breast; Breast Cancer Patient; Cancer Patient; Carcinoma; Cells; Clinic; Clinical; Clinical Data; Clonal Evolution; Community Clinical Oncology Program; Comprehensive Cancer Center; Core Biopsy; Data; Development; Disease; Dissection; Elements; Evolution; Exhibits; Fibroblasts; Gene Frequency; Genes; Genomics; Granulocyte Colony-Stimulating Factor; Hematology; Hematopoiesis; Hematopoietic; Incidence; Individual; Infiltration; Investigation; Lymphocyte; Mammary Neoplasms; Methods; Modeling; Molecular; Mutate; Mutation; Myelogenous; Myeloproliferative disease; Neoadjuvant Therapy; Newly Diagnosed; Oncogenic; Organ; Patients; Pattern; Population; Prediction of Response to Therapy; Prevalence; Prior Chemotherapy; Radiation therapy; Recurrence; Regression Analysis; Resolution; Role; Sampling; Solid Neoplasm; Specimen; Stress; Testing; Therapeutic; Time; Tissues; Toxic effect; Treatment outcome; age related; chemotherapy; clinical practice; clinical sequencing; clinical translation; cohort; cytotoxic; deep sequencing; fitness; genomic predictors; granulocyte; hematopoietic stem cell expansion; high risk; hormone therapy; insight; novel; peripheral blood; permissiveness; prognostic; prospective; response; sample collection; side effect; single cell analysis; therapy development; treatment strategy; tumor; tumor microenvironment

PROJECT SUMMARY/ABSTRACT Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related expansion of hematopoietic stem cells that harbor somatic alterations without presenting other hematologic abnormalities. CHIP has been detected in normal peripheral blood of cancer patients with solid tumors and has been suggested to have a permissive role in therapy-related secondary myeloid disease development. Our recent analysis of clinical sequencing of 113,079 solid tumor specimens demonstrated that CHIP clones are also present in the solid tumor microenvironment due to admixed mutated hematopoietic elements; however, enrichment of admixed CHIP, its evolution under therapy, and its clinical impact on solid tumor treatment are poorly understood. In this proposal, we will characterize CHIP in the context of breast invasive carcinoma, which is treated with chemotherapeutics in both adjuvant and neoadjuvant settings and has been shown to have prognostic interactions with infiltrating hematopoietic cells in its microenvironment. We hypothesize that CHIP exhibits a distinct genomic landscape when enriched in breast tumor microenvironment, evolves under breast tumor treatment, and is correlated with the development of therapy-induced hematological toxicity. To test these hypotheses, we will assemble a cohort of 1,200 newly diagnosed breast cancer patients, collect comprehensive clinical data as well as sequential pre- and post-treatment peripheral blood and breast tumor samples, and profile CHIP at high resolution in three aims. First, we will determine the mutational spectrum of admixed CHIP before breast tumor treatment. Using high-depth sequencing of peripheral blood and breast tumor samples, we will detect CHIP mutations at >0.1% allele frequency and correlate the prevalence of admixed CHIP with the level of infiltrating lymphocytes and other hematopoietic markers. Using single-cell genomic analysis, we will resolve the number of exclusive CHIP clones. Second, we will profile CHIP after chemotherapy in peripheral blood – and breast tumor samples in neoadjuvant settings – to study its evolution by assessing mutation-specific fitness and therapeutic bottleneck size, using hormonal therapy as control. We will also investigate the effect of granulocyte-colony stimulation on CHIP's clonal dynamics. Longitudinal peripheral blood sampling will elucidate the long-term evolution of CHIP 1-2 years after the end of breast tumor's treatment. Third, we will develop a statistical regression model to determine the distinct CHIP clones that may be correlated with clinical response and development of therapy-induced hematological toxicity. This study is novel in its utilization of systematically collected clinical and high-resolution molecular data, and it will provide insight on CHIP's clonal evolution under breast tumor treatment. Moreover, it will illustrate the significance of molecularly defined clonal analysis of hematopoietic populations as a fundamental predictor of therapy-induced hematological complications. Finally, it will establish a platform for long-term clinical and molecular inquiries of CHIP's progression to therapy-related myeloid neoplasms in high-risk patients.

项目摘要/摘要 未确定潜能克隆性造血(CHIP)是一种与年龄相关的造血干扩增 有体细胞变化而不出现其他血液异常的细胞。芯片已经被 在患有实体瘤的癌症患者的正常外周血中检测到，并被认为有一种 在与治疗相关的继发性髓系疾病发展中的许可作用。我们最新的临床分析 对113,079个实体肿瘤标本的测序表明，固体中也存在芯片克隆 混合突变的造血元素所致的肿瘤微环境；然而，混合的 芯片，它在治疗下的演变，以及它对实体肿瘤治疗的临床影响，人们知之甚少。 在这项提案中，我们将在乳腺浸润性癌的背景下描述CHIP的特征，这种癌症是用 化疗药物在佐剂和新佐剂环境中都有，并已被证明具有预后作用 在其微环境中与浸润性造血细胞的相互作用。我们假设芯片显示出一个 独特的基因组图谱在乳腺肿瘤微环境中丰富时，在乳腺肿瘤下进化 治疗，并与治疗引起的血液学毒性的发展有关。为了测试这些 假设，我们将汇集1200名新诊断的乳腺癌患者，收集 全面的临床资料以及治疗前后的外周血象和乳腺肿瘤的序贯 样品，以及三个目标的高分辨率轮廓芯片。首先，我们将确定基因的突变谱 乳腺肿瘤治疗前掺加芯片。利用外周血和乳房的高深度测序 肿瘤样本，我们将检测&gt；0.1%等位基因频率的芯片突变，并将 掺加芯片检测浸润性淋巴细胞等造血标志物的水平。使用单电池 基因组分析，我们将解析独家芯片克隆的数量。其次，我们将对芯片进行剖析后 外周血化疗--以及新辅助环境下的乳腺肿瘤标本--研究其演变 通过评估突变特异性适合性和治疗瓶颈大小，以激素治疗为对照。我们 还将研究粒细胞集落刺激对芯片克隆动力学的影响。纵向 外周血采样将阐明CHIP在乳房终止后1-2年的长期演变 肿瘤的治疗。第三，我们将开发一个统计回归模型来确定不同的芯片克隆 这可能与临床反应和治疗引起的血液毒性的发展有关。 这项研究在利用系统收集的临床和高分辨率分子数据方面是新颖的， 这将为研究乳腺肿瘤治疗下芯片的克隆进化提供依据。此外，它还将说明 分子定义的造血群体克隆分析作为基本预测指标的意义 治疗引起的血液并发症。最后，它将建立一个长期临床和 高危患者CHIP进展为治疗相关髓系肿瘤的分子研究。