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：
10198123
负责人：
KATHERINE A. HOADLEY
金额：
$ 59.72万
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/10198123
关键词：
African American Age BRCA1 gene Base Excision Repairs Biological 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 Equilibrium Expression Profiling Formalin Frequencies Gene Expression Genetic Genetic Recombination Genetic Transcription Genome Stability Genomic Instability Goals Health Services Accessibility Human Immune Immune response Immunologic Markers Immunology procedure Investigation Lead 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 Prognosis Prognostic Marker Proteins RNA Race Reproductive History Research Resources Role Sampling Source Specimen TP53 gene Tissues Tumor Biology Variant Woman base black patient black women chemotherapy cohort genetic variant genome wide association study genome-wide health care availability homologous recombination immune activation malignant breast neoplasm mortality mortality disparity mutant mutational status novel novel marker pleiotropism population based precision medicine predictive marker protein biomarkers protein profiling public health intervention repaired response survivorship therapy resistant tumor tumor progression

African American Age BRCA1 gene Base Excision Repairs Biological 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 Equilibrium Expression Profiling Formalin Frequencies Gene Expression Genetic Genetic Recombination Genetic Transcription Genome Stability Genomic Instability Goals Health Services Accessibility Human Immune Immune response Immunologic Markers Immunology procedure Investigation Lead 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 Prognosis Prognostic Marker Proteins RNA Race Reproductive History Research Resources Role Sampling Source Specimen TP53 gene Tissues Tumor Biology Variant Woman base black patient black women chemotherapy cohort genetic variant genome wide association study genome-wide health care availability homologous recombination immune activation malignant breast neoplasm mortality mortality disparity mutant mutational status novel novel marker pleiotropism population based precision medicine predictive marker protein biomarkers protein profiling public health intervention repaired response survivorship therapy resistant tumor tumor progression

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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

项目摘要/摘要基因组稳定性由多个DNA修复途径确定，包括容易出错和无误差机制。突变可能是由于DNA修复途径失活（例如BRCA1缺陷）或容易发生修复的病理激活。肿瘤抑制p53对这种平衡具有多效性影响。它与基础切除修复（BER）物理相互作用，调节核苷酸切除修复（NER），并且调节不匹配维修（MMR）。野生型p53可能会抑制容易发生的误差，但不能抑制无错误的非同理结束加入（NHEJ），并可以调节同源重组（HR）。最近，P53的新角色有已识别，例如在ApoBec3b激活中的作用。许多机械研究研究了该复合物 p53在DNA修复中的作用，但对人类肿瘤的大规模研究很少研究P53和DNA修复人类肿瘤中的途径功能，甚至更少的人通过种族评估了这些关系。更精致现在可以了解p53损失，DNA修复和突变特征之间的关系由于：（1）突变特征的出现，这可以提供功能效应的DNA证据和平衡多个误差和无误差DNA修复途径；（2）最近的改进来自福尔马林固定石蜡嵌入（FFPE）样品的表达分析。这些进步对了解乳腺癌的死亡率差异，因为它们可以在基于人群的大规模研究资源。我们以前基于人群的研究表明，p53突变在非洲中更为普遍美国乳腺癌患者（白人乳腺癌患者中有60％p53突变体和35％）。此外， DNA修复对于对化疗的反应至关重要，这都是由于DNA修复对化学疗法的直接影响抗性和间接对免疫反应激活的影响。当前项目将使用一个集成评估人类肿瘤中p53相关的DNA修复途径不规则的方法，测量两个RNA 表达和突变特征（AIM 1A）。然后，将评估p53损失和DNA修复不平衡使用RNA和基于蛋白质的空间测定的免疫标记物（AIM 1B）与免疫激活有关。这些分析将利用卡罗来纳州乳腺癌研究（CBC），该研究对3000名乳房女性过采样黑人妇女（50％黑人妇女，n = 1500）。更好地了解种系 DNA修复中黑白差异的决定因素，现有的基因组宽SNP数据将用于识别与DNA修复失衡和免疫反应有关的遗传变异（AIM 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以引起癌症的进展和化学抗性。这些途径的阐明是一步的关键步骤确定临床和公共卫生干预措施以降低死亡率差异。 1