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

基本信息

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
项目类别：
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

项目摘要

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

项目概要/摘要基因组稳定性由多种 DNA 修复途径决定，包括易错和无错途径机制。突变可能是由 DNA 修复途径失活（例如 BRCA1 缺陷）或由易错修复的病理激活。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) 发生物理相互作用，调节核苷酸切除修复 (NER)，并且调节错配修复 (MMR)。野生型p53可能抑制易错的，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 的新角色出现了已被鉴定，例如在 APOBEC3B 激活中的作用。许多机制研究已经研究了复杂的 p53 在 DNA 修复中的作用，但很少有针对人类肿瘤的大规模研究调查 p53 和 DNA 修复人类肿瘤中的通路功能，很少有人按种族评估这些关系。更精致的现在可以了解 p53 丢失、DNA 修复和突变特征之间的关系由于：(1) 突变特征的出现，可以提供功能效应的 DNA 证据，平衡多个易错和无错 DNA 修复途径； (2) 最近的改进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差异，因为它们使得基于人群的大规模研究成为可能资源。我们之前基于人群的研究表明，p53 突变在非洲更为常见美国乳腺癌患者（p53 突变体占 60%，白人乳腺癌患者为 35%）。此外， DNA 修复对于化疗反应至关重要，这都是由于 DNA 修复对化疗的直接影响抵抗力以及对免疫反应激活的间接影响。本项目将采用综合评估人类肿瘤中 p53 相关 DNA 修复途径不规则性的方法，测量 RNA 表达和突变特征（目标 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测定来研究与免疫激活的关系（目标 1b）。这些分析将利用卡罗莱纳州乳腺癌研究 (CBCS)，该研究对 3000 名患有乳腺癌的女性进行了研究黑人女性过度采样的癌症（50% 黑人女性，n=1500）。为了更好地了解种系 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（目标 2）。这项调查将确定在 p53 突变状态和种族的背景下，关键的 DNA 修复和免疫途径相互作用，导致癌症进展和化疗耐药性。阐明这些途径是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异。 1