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: 10385785
• 负责人: KATHERINE A. HOADLEY
• 金额: $ 60.05万
• 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/10385785
• 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; 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; 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; prognosis biomarker; protein biomarkers; protein profiling; public health intervention; repaired; response; survivorship; therapy resistant; 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/文摘