Mentored Clinical Scientist Research Career Development Award (Parent K08)

指导临床科学家研究职业发展奖（家长K08）

• 批准号: 9647288
• 负责人: Thomas Paul Slavin
• 金额: $ 24.9万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9647288
• 关键词: ATM Gene Mutation; Aftercare; Age; Alleles; BRCA1 gene; BRCA2 gene; Biological Assay; Biological Factors; Blood; Blood Cells; Bone Marrow; CD34 gene; CHEK2 gene; Cardiovascular Diseases; Cells; Cessation of life; Chromosomal Instability; Chromosome Breakage; Cities; Clinical; Clonal Evolution; Clone Cells; Communities; Counseling; Cytotoxic Chemotherapy; DNA Damage; DNA Double Strand Break; DNA Repair; DNA Sequence Alteration; DNA sequencing; Data; Databases; Defect; Development; Disease; Electronic Health Record; Engraftment; European; Evolution; Exposure to; Foundations; Frequencies; General Population; Genes; Genetic screening method; Genomic Instability; Germ-Line Mutation; Goals; Heart Diseases; Hematologic Neoplasms; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Hereditary Breast Carcinoma; Hereditary Malignant Neoplasm; Human; Immune; Individual; K-Series Research Career Programs; Knowledge; Link; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Medical; Mentors; Molecular Cloning; Mosaicism; Mus; Mutation; Parents; Patients; Phosphotransferases; Population; Population Study; Predisposing Factor; Predisposition; Prevalence; Prospective cohort; Radiation; Recommendation; Relapse; Research; Risk; Risk Assessment; Sampling; Scientist; TP53 gene; Testing; Time; Transplantation; Treatment-Related Cancer; Tumor Burden; Variant; Woman; alpha-Thalassemia; base; bone cell; cancer genomics; cardiovascular disorder risk; chemotherapy; clinical predictors; clinically significant; cytotoxic; erythritol anhydride; exome sequencing; experimental study; genetic variant; leukemia; malignant breast neoplasm; mortality; mouse model; mutation carrier; neoplasm registry; next generation; novel; patient population; precision medicine; prevent; prospective; response; self-renewal; survivorship; tumor

PROJECT SUMMARY Genetic testing has made it possible to identify individuals with germline predisposition to cancer, e.g., carriers of ATM, BRCA1, TP53 mutations. In addition to an increased risk of developing primary cancer, germline mutation carriers may develop post-treatment-related malignancies (i.e., therapy-related leukemias), which develop as new primary malignancies, rather than as relapse of the original tumors. I have recently shown that germline mutation carriers may be at an increased risk of clonal hematopoiesis of indeterminate potential (CHIP). CHIP is defined as somatic expanded blood cell clones in individuals without other hematologic disease. CHIP is identified by gene variants found on next-generation DNA sequencing assays that are present at very low frequency. These variants do not represent the germline, hematologic malignancy, post-zygotic mosaicism, or circulating tumor burden. CHIP rates in healthy populations have been estimated to be 2% in those under the age of 60, and increase with age and/or exposure to chemotherapy. The clinical significance of CHIP lies in the increased risks for cardiovascular disease, primary and secondary leukemias, other hematologic malignancies, and in general for all-cause mortality. I have recently gained data supporting the notion that ATM mutations represent a novel germline predisposing factor to CHIP. In fact, I have shown that heterozygous ATM germline mutation carriers: 1) are relatively frequent in the general population of healthy individuals (1 in 263 individuals of European ancestry) and women with familial breast cancer (1.5 in 100 individuals); 2) have an apparent increased rate of CHIP as compared to non-ATM mutation carriers; and 3) may have unique molecular CHIP signatures. Therefore, ATM germline mutations are common and may predispose to CHIP. ATM regulates the DNA damage response to double-strand DNA breaks through its kinase activity. Due to ATM haplo-insufficiency and DNA-repair defect predisposition, I postulate that ATM germline mutation carriers may not have the proper mechanisms of DNA repair and therefore cannot prevent CHIP, particularly after cytotoxic therapy (chemotherapy or radiation). Guided by my preliminary data, I will test the hypothesis that ATM germline mutations are associated with and predispose hematopoietic cells to develop CHIP. I will test my hypothesis through the following Specific Aims: 1) to identify the clinical and biologic factors associated with ATM germline mutations and CHIP and lay the foundation for prospective population-based studies, 2) to explore chromosomal instability and dynamics of CHIP in a prospective cohort of ATM germline mutation carriers, and 3) determine if CHIP can be recapitulated in a mouse model and predict clinical malignant evolution in ATM mutation carriers. In summary, CHIP may pose a notable risk for ATM mutation carriers and determination of how it arises and what drives its progression is necessary to counsel, screen and manage this patient population appropriately.

项目总结 基因检测使识别具有癌症遗传易感性的个体成为可能，例如携带者 ATM、BRCA1、TP53突变。除了罹患原发癌症的风险增加外，生殖系 突变携带者可能会发展为治疗后相关的恶性肿瘤(即治疗相关的白血病)，这 发展为新的原发恶性肿瘤，而不是作为原始肿瘤的复发。我最近证明了 生殖系突变携带者可能有更高的风险进行不确定潜能克隆性造血(CHIP)。 CHIP被定义为在没有其他血液疾病的个体中进行体细胞扩增的克隆。芯片 是通过在新一代DNA测序分析中发现的基因变异来鉴定的，这些基因变异的水平非常低 频率这些变异不代表生殖系、血液系统恶性肿瘤、合子后嵌合体或 循环中的肿瘤负担。据估计，健康人群的芯片率在以下人群中为2% 60岁，并随着年龄和/或接受化疗而增加。芯片的临床意义在于 心血管疾病、原发和继发性白血病、其他血液系统恶性肿瘤的风险增加， 总的来说，是各种原因造成的死亡。我最近获得了支持ATM突变的数据 代表了一种新的生殖系芯片易感因子。事实上，我已经证明了ATM机的杂合生殖系 突变携带者：1)在健康人群中相对常见(263人中有1人 欧洲血统)和患有家族性乳腺癌的妇女(每100人中有1.5人)；2)有明显的 与非ATM突变携带者相比，芯片率增加；以及3)可能具有独特的分子芯片 签名。因此，ATM胚系突变是常见的，并可能易患上CHIP。ATM规定了 对双链DNA的DNA损伤反应突破了它的激酶活性。由于自动柜员机单点不足 和DNA修复缺陷的倾向，我推测ATM生殖系突变携带者可能没有适当的 DNA修复的机制，因此不能阻止芯片，特别是在细胞毒治疗之后 (化疗或放射治疗)。以我的初步数据为指导，我将检验ATM生殖系 突变与造血细胞相关，并使其易于形成芯片。我会检验我的假设 通过以下具体目标：1)确定与ATM生殖系相关的临床和生物学因素 突变和芯片，为未来的基于人群的研究奠定基础，2)探索染色体 ATM生殖系突变携带者的预期队列中芯片的不稳定性和动力学，以及3)决定 芯片可以在小鼠模型中重现，并预测ATM突变携带者的临床恶性演变。 总之，芯片可能会对ATM突变携带者构成显著风险，并确定它是如何产生和 推动其进展的是对这一患者群体进行适当咨询、筛查和管理的必要因素。