Germline Genetic Modifiers of Radiation Response

辐射反应的种系遗传修饰剂

• 批准号: 10741022
• 负责人: John Tyson McDonald
• 金额: $ 40.11万
• 依托单位: SRI INTERNATIONAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10741022
• 关键词: Acute; Address; Affect; African American; Aftercare; Age; Algorithms; Alleles; American; Animal Model; Biological; Biological Assay; Breast; Breast Cancer Patient; Cancer Patient; Cancer Survivor; Caucasians; Cell Culture Techniques; Cell Cycle; Cell Line; Cells; Clinical; Clinical Data; Clustered Regularly Interspaced Short Palindromic Repeats; Code; Correlation Studies; DNA; DNA sequencing; Data; Dermal; Diagnosis; Epithelial Cells; European; Exons; Exposure to; Frequencies; Gene Expression; Gene Frequency; Genes; Genetic; Genomics; Genotype; Germ-Line Mutation; Goals; Health; In Vitro; Incidence; Individual; Individual Differences; Inflammatory; Investigation; Ionizing radiation; Libraries; Life; Link; Malignant Neoplasms; Malignant neoplasm of prostate; Mammary Gland Parenchyma; Measures; Modeling; Mutagens; Mutation; NF1 gene; Normal Cell; Normal tissue morphology; Outcome; PALB2 gene; Pathway interactions; Patients; Phenotype; Population; Precision therapeutics; Proliferating; Prostate; Quality of life; Radiation; Radiation Dose Unit; Radiation Oncology; Radiation Tolerance; Radiation Toxicity; Radiation exposure; Radiation induced damage; Radiation therapy; Radiation-Induced Gene Expression; Radiobiology; Reporting; Research Project Grants; Risk; Sampling; Single Nucleotide Polymorphism; Statistical Models; Surveys; Testing; Toxic effect; United States; United States National Institutes of Health; Variant; Woman; caucasian American; clinically relevant; cohort; combinatorial; cytokine; design; exome; expectation; fitness; genetic variant; genomic locus; improved; in vitro testing; inter-individual variation; interpatient variability; ionization; irradiation; knockout gene; malignant breast neoplasm; medical complication; men; mortality; neoplasm registry; next generation sequencing; novel; poor health outcome; protein function; radiation resistance; radiation response; radioresistant; response; risk variant; screening; senescence; side effect; survivorship; tissue injury; transcriptome; transcriptome sequencing; transcriptomics; treatment response; triple-negative invasive breast carcinoma; tumor; whole genome

Approximately 50% of cancer patients receiving ionizing radiation suffer from radiation-induced normal tissue injury that significantly affects quality of life and presents potentially life-threatening consequences in 5-10% of the cases. Due to a large range of interpatient variability, the amount of radiation delivered to all patients is largely guided by the tolerance of more radiosensitive individuals. Significant associations with biological genetic determinates of interpatient variability to radiation responses from alleles with differing frequencies by population ancestry will form the basis of our study. A better understanding of genetic factors that might contribute to a deterministic radiation response would mitigate unwanted medical complications. The a priori identification of genetic variants associated with increased radiation damage would be immensely useful for optimizing radiation dose through predictive screening to allow creation of novel patient cohorts. We will use an in vitro approach and apply genomics, transcriptomics, and functional modeling towards advanced determination of individual genotypes most at risk for enhanced radiation sensitivity. An in-house panel of 100 normal-tissue derived epithelial cell cultures from prostate and breast cancer patients will be used with exposure to ionizing irradiation. A focus on individuals with differing genetic ancestry will be used for this purpose. Radiation response will be quantified individually and in groups as continuous variables dependent on genetic variants and gene expression following radiation exposure in association with statistical modeling to find genetic loci and epistatic SNP-SNP interactions. In order to enlarge the scope and clinical relevance of our study, we will correlate our findings to previously acquired germline DNA samples from patients treated with radiation with available clinical data as well as radiation toxicity scores. The specific aims are: 1) to quantify the association of interpatient radiation resistance and sensitivity with polygenic exome coding germline variants and gene expression using a radiation associated senescence-associated secretory phenotype that is associated with pro-inflammatory cytokines and 2) screen DNA samples from radiation therapy patients with known toxicity scores and perform preliminary functional testing to modulate radiation sensitivity in vitro for germline radiation associated variants. The results of this proposal will provide a novel platform to screen for predictive variants in animal models and patients. This will bring us one step closer to genomically guided radiation treatment and enable the investigation novel mechanisms involved in radiation sensitivity.

大约50%接受电离辐射的癌症患者遭受辐射诱导的正常组织 严重影响生活质量的伤害，并在5-10%的人中表现出潜在的危及生命的后果 案件。由于患者间的变异性范围很大， 这主要是由对辐射敏感的个体的耐受性决定的。与生物遗传学显著相关 不同人群不同频率等位基因辐射反应患者间变异性的测定 祖先是我们研究的基础。更好地了解可能导致癌症的遗传因素 确定性辐射响应将减轻不希望的医疗并发症。先验识别 与辐射损伤增加相关的遗传变异将对优化辐射 通过预测性筛选确定剂量，以创建新的患者队列。我们将使用体外方法， 将基因组学、转录组学和功能建模应用于个体的高级确定， 基因型对辐射敏感性增强的风险最大。一个由100个正常组织来源的 来自前列腺癌和乳腺癌患者的上皮细胞培养物将与暴露于电离辐射一起使用。 为此目的，将重点关注具有不同遗传祖先的个体。辐射反应将是 根据遗传变异和基因表达作为连续变量单独和分组量化 在辐射暴露后，与统计建模相关联，以找到遗传位点和上位性SNP-SNP 交互.为了扩大我们研究的范围和临床相关性，我们将把我们的发现与 先前从接受放射治疗的患者中获得的生殖系DNA样本， 以及辐射毒性评分。具体目标是：1）量化患者间辐射的关联 用多基因外显子编码种系变体和使用辐射的基因表达的抗性和敏感性 与促炎细胞因子相关的衰老相关分泌表型， 2)从具有已知毒性评分的放射治疗患者中筛选DNA样本，并进行初步的 功能测试，以调节生殖系辐射相关变体的体外辐射敏感性。结果 该提案的一部分将提供一个新的平台来筛选动物模型和患者中的预测性变体。这 将使我们更接近基因组引导的放射治疗，并使研究新颖， 辐射敏感性的机制。