P53, DNA Repair Imbalance, and Immune Response in Breast Cancer Mortality Disparities

P53、DNA 修复失衡和乳腺癌死亡率差异中的免疫反应

• 批准号: 10594967
• 负责人: KATHERINE A. HOADLEY
• 金额: $ 59.16万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-06 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10594967
• 关键词: African American; African American population; Age; BRCA1 gene; Base Excision Repairs; Biological; Black race; Breast Cancer Patient; Cancer Etiology; Chemoresistance; Clinical; Complex; DNA; DNA Repair; DNA Repair Gene; DNA Repair Pathway; DNA Sequence Alteration; DNA sequencing; Data; Defect; Development; Disparity; Equilibrium; Expression Profiling; Formalin; Frequencies; Gene Expression; Genes; Genetic; Genetic Recombination; Genetic Transcription; Genome Stability; Genomic Instability; Germ-Line Mutation; Goals; Health Services Accessibility; Human; Immune; Immune response; Immunologic Markers; Immunology procedure; Investigation; Link; Malignant Neoplasms; Measures; Methods; Mismatch Repair; Mutate; Mutation; Nonhomologous DNA End Joining; Nucleotide Excision Repair; Obesity; Paraffin Embedding; Pathologic; Pathway interactions; Patients; Pattern; Phenotype; Population Study; Prevalence; Process; Prognostic Marker; Proteins; RNA; Race; Reproductive History; Research; Resources; Role; Sampling; Source; Specimen; TP53 gene; Tissues; Tumor Biology; Variant; Woman; black patient; black women; chemotherapy; cohort; genetic variant; genome wide association study; genome-wide; health care availability; homologous recombination; immune activation; improved; malignant breast neoplasm; mortality; mortality disparity; mutant; mutational status; novel; novel marker; pleiotropism; population based; precision medicine; predictive marker; prognosis biomarker; protein biomarkers; protein profiling; public health intervention; repaired; response; survivorship; therapy resistant; treatment response; tumor; tumor progression

PROJECT SUMMARY/ABSTRACT Genome stability is determined by multiple DNA repair pathways, including both error-prone and error-free mechanisms. Mutations can be caused by inactivation of DNA repair pathways (e.g. BRCA1 defects) or by pathological activation of error-prone repair. The tumor suppressor p53 has pleiotropic effects on this balance. It physically interacts with base excision repair (BER), modulates nucleotide excision repair (NER), and regulates mismatch repair (MMR). Wild type p53 may inhibit error prone, but not error-free non-homologous end joining (NHEJ), and can modulate homologous recombination (HR). Recently, new roles for p53 have been identified, such as a role in APOBEC3B activation. Many mechanistic studies have studied the complex roles of p53 in DNA repair, but few large-scale studies of human tumors have investigated p53 and DNA repair pathway function in human tumors, and even fewer have evaluated these relationships by race. A more refined understanding of the relationships between p53 loss, DNA repair, and mutational signatures is now possible due to: (1) the advent of mutational signatures, which can provide DNA evidence of the functional effects and balance across multiple error prone and error free DNA repair pathways; and (2) recent improvements in expression profiling from formalin-fixed paraffin embedded (FFPE) samples. These advances are important for understanding breast cancer mortality disparities because they enable broad scale study in population-based resources. Our previous population-based studies have shown that p53 mutations are more common in African American breast cancer patients (60% p53 mutant vs. 35% among white breast cancer patients). Furthermore, DNA repair is critical for response to chemotherapy, both due to direct effects of DNA repair on chemotherapy resistance, and indirect effects on activation of immune responses. The current project will use an integrative approach to evaluate p53-related DNA repair pathway irregularities in human tumors, measuring both RNA expression and mutational signatures (Aim 1a). Then, p53 loss and DNA repair imbalance will be evaluated in relation to immune activation using both RNA and protein-based, spatial assays of immune markers (Aim 1b). These analyses will leverage, the Carolina Breast Cancer Study (CBCS), a study of 3000 women with breast cancer that oversampled black women (50% black women, n=1500). To better understand the germline determinants of black-white differences in DNA repair, existing genome wide SNP data will be used to identify genetic variants linked with DNA repair imbalance and immune response (Aim 2). This investigation will identify key DNA repair and immune pathways, in context of p53 mutation status and race, that interact to cause cancer progression and chemoresistance. The elucidation of these pathways is a key underlying step in identifying clinical and public health interventions to reduce mortality disparities. 1

项目总结/摘要 基因组的稳定性是由多种DNA修复途径决定的，包括易错和无错两种 机制等突变可由DNA修复途径失活（例如BRCA 1缺陷）或由 错误修复的病理激活。肿瘤抑制因子p53对这种平衡具有多效性作用。 它与碱基切除修复（BER）相互作用，调节核苷酸切除修复（NER）， 调节错配修复（MMR）。野生型p53可以抑制易错的，但不能抑制无错的非同源的 末端连接（NHEJ），并且可以调节同源重组（HR）。最近，p53的新角色已经 例如，在APOBEC 3B激活中的作用。许多机理研究已经研究了复合物 p53在DNA修复中的作用，但很少有大规模的人类肿瘤研究调查了p53和DNA修复 通路在人类肿瘤中的功能，甚至很少有人通过种族来评估这些关系。更精致的 了解p53丢失、DNA修复和突变特征之间的关系现在是可能的 由于：（1）突变签名的出现，它可以提供功能效应的DNA证据， 多个易错和无错DNA修复途径之间的平衡;和（2）最近的改进， 来自福尔马林固定石蜡包埋（FFPE）样品的表达谱。这些进步对于 了解乳腺癌死亡率的差异，因为它们使基于人群的大规模研究成为可能。 资源我们以前的基于人群的研究表明，p53突变在非洲人中更常见。 美国乳腺癌患者（60% p53突变体对白色乳腺癌患者中的35%）。此外，委员会认为， DNA修复对于化疗的反应至关重要，这两者都是由于DNA修复对化疗的直接影响 抗性和对免疫应答激活的间接影响。本项目将采用综合 一种评估人类肿瘤中p53相关DNA修复途径不规则性的方法， 表达和突变签名（Aim 1a）。然后，将评估p53丢失和DNA修复失衡， 使用基于RNA和蛋白质的免疫标记物空间分析与免疫激活的关系（目的1b）。 这些分析将利用卡罗莱纳乳腺癌研究（CBCS），一项对3000名乳腺癌患者的研究。 对黑人女性进行过采样的癌症（50%黑人女性，n=1500）。为了更好地了解生殖系 DNA修复中黑白差异的决定因素，现有的全基因组SNP数据将用于识别 与DNA修复失衡和免疫反应相关的遗传变异（Aim 2）。这次调查将确定 关键的DNA修复和免疫途径，在p53突变状态和种族的背景下，相互作用导致 癌症进展和化学抗性。这些途径的阐明是一个关键的基础步骤， 确定临床和公共卫生干预措施，以减少死亡率差距。 1