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）

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要基因检测使鉴定出生殖线易感癌症的个体，例如携带者 ATM，BRCA1，TP53突变。除了增加原发性癌症的风险外，种系突变携带者可能会出现与治疗后相关的恶性肿瘤（即与治疗相关的白血病）发展为新的原发性恶性肿瘤，而不是原始肿瘤的复发。我最近表明种系突变载体可能会增加不确定潜力（CHIP）的克隆造血的风险。 CHIP定义为在没有其他血液学疾病的个体中体细胞的血细胞克隆。芯片通过在非常低的下一代DNA测序测定中发现的基因变体鉴定频率。这些变体不代表种系，血液学恶性肿瘤，杂志后镶嵌或循环肿瘤负担。据估计，健康人群中的芯片率为2％年龄为60岁，并随着年龄和/或接触化学疗法而增加。芯片的临床意义在于心血管疾病，原发性和继发性白血病，其他血液系统恶性肿瘤的风险增加，通常，全因死亡率。我最近获得了支持ATM突变的观点的数据代表一种新型的种系易于芯片。实际上，我已经证明了杂合的ATM种系突变载体：1）在健康个体的一般人群中相对较常见（263个个体中有1个欧洲血统）和家族性乳腺癌的妇女（100人中有1.5人）； 2）明显与非ATM突变载体相比，芯片速率提高； 3）可能具有独特的分子芯片签名。因此，ATM种系突变很常见，可能会易于芯片。 ATM调节对双链DNA的DNA损伤反应通过其激酶活性中断。由于ATM不适和DNA修复缺陷倾向，我假设ATM种系突变携带者可能没有适当的 DNA修复的机制，因此无法防止芯片，特别是在细胞毒性治疗后（化学疗法或放射线）。在我的初步数据的指导下，我将测试ATM种系的假设突变与造血细胞相关并易于发展碎屑。我将检验我的假设通过以下特定目的：1）确定与ATM种系有关的临床和生物学因素突变和芯片并为前瞻性人群研究奠定了基础，2）探索染色体 ATM种系突变载体的前瞻性队列中芯片的不稳定性和动力学，3）确定是否是否可以在小鼠模型中概括芯片，并预测ATM突变载体中的临床恶性进化。总而言之，芯片可能会构成ATM突变载体的明显风险，并确定其出现的状态和适当地咨询，筛查和管理该患者人群的咨询需要的是必要的。