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

项目摘要/摘要 基因组的稳定性是由多条DNA修复途径决定的，包括易出错和无错修复 机械装置。突变可由DNA修复途径的失活(例如BRCA1缺陷)或 易出错修复的病理性激活。肿瘤抑制因子P53对这种平衡具有多效性。 它与碱基切除修复(BER)相互作用，调节核苷酸切除修复(NER)，以及 调节错配修复(MMR)。野生型p53可能抑制易出错的，但不是无错的非同源的 末端连接(NHEJ)，并可调节同源重组(HR)。最近，P53的新角色已经 已经确定，例如在APOBEC3B激活中发挥作用。许多力学研究都对这种复合体进行了研究 P53在DNA修复中的作用，但很少有大规模的人类肿瘤研究研究P53和DNA修复 途径在人类肿瘤中的作用，更少的人通过RACE来评估这些关系。一个更精致的 现在有可能理解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，它可以提供功能效应的DNA证据和 平衡多个容易出错和无错的DNA修复途径；以及(2)最近在 福尔马林固定石蜡包埋(FFPE)样本的表达谱。这些进展对 了解乳腺癌死亡率差异是因为它们能够在以人群为基础的大范围研究中 资源。我们之前的基于人群的研究表明，p53突变在非洲更常见 美国乳腺癌患者(60%为p53突变，而白人乳腺癌患者为35%)。此外， DNA修复是化疗反应的关键，这两者都是由于DNA修复对化疗的直接影响 抗药性，以及对免疫反应激活的间接影响。当前项目将使用一个集成的 一种评估人类肿瘤中与P53相关的DNA修复途径异常的方法 表达和突变特征(目标1a)。然后，P53丢失和DNA修复失衡将在 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(目标1b)。 这些分析将利用卡罗莱纳州乳腺癌研究(CBCS)，这是一项对3000名患有乳房的女性的研究 过多抽样黑人妇女的癌症(50%黑人妇女，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(目标2)。这项调查将确定 与P53突变状态和种族相关的关键DNA修复和免疫通路，它们相互作用导致 癌症进展和化疗耐药。对这些途径的阐明是 确定临床和公共卫生干预措施，以减少死亡率差距。 1

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