Characterization of DNA repair in genomic and transcriptomic evolution of early lung carcinogenesis

早期肺癌基因组和转录组进化中 DNA 修复的表征

• 批准号: 10257801
• 负责人: Catherine Rufatto Sears
• 金额: --
• 依托单位: RLR VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10257801
• 关键词: Adenocarcinoma; Archives; Atypical adenomatous hyperplasia; Benign; Biological Assay; Biological Markers; Cancer Etiology; Carcinogens; Carcinoma; Cells; Cessation of life; Characteristics; Chronic; Complement; Complex; DNA Repair; DNA Repair Gene; DNA Repair Pathway; Data; Detection; Development; Diagnosis; Diagnostic; Disease; Dysplasia; Early Diagnosis; Early treatment; Environment; Epigenetic Process; Epithelial Cells; Ethics; Evolution; Excision; Gene Expression; Genomic Instability; Genomics; Goals; Head and neck structure; Histologic; Histopathologic Grade; Human; Human Characteristics; Immune; Immune Evasion; Immunologics; Immunophenotyping; Immunotherapy; In Vitro; Indolent; Intervention; Intraepithelial Neoplasia; Knowledge; Laboratories; Lead; Lesion; Lung; Lung Adenocarcinoma; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Masks; Modeling; Mus; Mutation; Nodule; Non-Malignant; Non-Small-Cell Lung Carcinoma; Operative Surgical Procedures; PDL1 inhibitors; Pathologic; Patients; Pattern; Physiological; Public Health; Recommendation; Relative Risks; Resistance; Risk; Risk Reduction; Role; Sampling; Specimen; Squamous Cell; Squamous Cell Lung Carcinoma; Therapeutic; Therapeutic Intervention; Time; Treatment Efficacy; United States; Urethane; Validation; Veterans; Xeroderma Pigmentosum; base; bronchial epithelium; carcinogenesis; chest computed tomography; cigarette smoke; exposure to cigarette smoke; genome sequencing; genomic data; high risk; improved; in vivo; inter-individual variation; interest; low dose computed tomography; lung cancer screening; lung carcinogenesis; mortality; new therapeutic target; patient population; personalized diagnostics; personalized medicine; predictive signature; premalignant; prevent; programmed cell death ligand 1; response; screening; single cell sequencing; therapeutic target; tool; transcriptomics; tumor; whole genome

Project Summary/Abstract Lung cancer remains the leading cause of cancer-related mortality in the United States and is particularly problematic in U.S. veterans, who are at an increased risk for lung cancer resulting in approximately 5,500 excess veteran deaths per year. This is largely due to the late stage at which lung cancer is diagnosed. However, resection of pre-malignant and stage I non-small cell lung cancers (NSCLC) results in cure in most patients. Current recommendations include screening high-risk patients for lung cancer by low dose computed tomography (CT) of the chest due to a 20% relative risk reduction in mortality. However, debate exists on the patient population most likely to benefit from this intervention. Pre-malignant lesions such as atypical adenomatous hyperplasia and early lung adenocarcinomas, identified as nodules on chest CT, are often indistinguishable from benign nodules, which can lead to aggressive diagnostic and therapeutic interventions, and possibly harm, in patients with benign nodules or delayed diagnosis in those with NSCLC. Better diagnostic and therapeutic targets are needed to detect and treat pre-malignant and early non-small cell lung cancers when cure is likely. A better understanding of the mechanisms underlying transition from pre-malignant to frankly malignant non-small cell lung cancers is essential for more accurate and timely diagnosis and ultimately improved survival. Genomic instability is a hallmark of cancer, and altered DNA repair pathways have been associated with increased risk of lung cancers. The DNA repair protein, Xeroderma Pigmentosum Group C (XPC) gene expression is decreased by chronic cigarette smoke in mice, and low XPC is identified early and often in human lung adenocarcinomas. Our laboratory has discovered a critical role of XPC in protection against development of cigarette smoke and carcinogen-induced lung adenocarcinoma development. We recently found that XPC protects against histologic progression of mouse NTCU-induced lung squamous cell carcinomas. Our preliminary data suggests progression of carcinogen-induced lung cancers in XPC deficient mice is associated with increasing copy genomic complexity with higher histologic grade. Based on these findings, we hypothesize that decreased DNA repair by XPC leads to pre-malignant lesions with characteristic mutational and epigenetic signatures that predict progression to lung cancer. We propose to study this in three aims, using human samples of pre-malignant and early NSCLC specimens complemented by our well-established, XPC-deficient urethane lung adenocarcinoma progression model. In Aim 1, we will identify the impact of XPC in transition from pre-malignant to early and late adenocarcinoma pathologic grades by performing single cell sequencing on specimens isolated from urethane-treated XPC deficient mice, and confirm orthologous changes in humans using archived genomic data (NCBI Gene Expression Omnibus) and mechanistic in vitro studies. In Aim 2, we will determine the mechanistic impact of immune evasion on lung carcinogenesis using PD-L1 inhibitor, atezolizumab, in our mouse lung adenocarcinoma progression model, and define characteristic immunogenotypic characteristics of atezolizumab-resistant lung adenocarcinomas. Finally, in Aim 3, we will determine the impact of DNA repair on critical genomic and epigenetic changes in pre-malignant and early human lung squamous cell carcinomas. DNA repair capacity, determined by host cell reactivation assay, will be compared to bronchial epithelial cell dysplasia regression or persistence, and clonal genomic and transcriptomic differences studied in dysplastic samples which progressed/persisted vs regressed. Studying the mechanisms and genomic instability in early NSCLC development may allow for earlier recognition and novel therapeutic targets in early non-small cell lung cancer.

项目总结/摘要 肺癌仍然是美国癌症相关死亡率的主要原因， 在美国退伍军人中存在问题，他们患肺癌的风险增加，导致大约5，500 每年都有大量的退伍军人死亡这在很大程度上是由于肺癌诊断的晚期阶段。然而，在这方面， 癌前病变和I期非小细胞肺癌（NSCLC）的切除导致大多数患者治愈。 目前的建议包括通过低剂量的计算， 胸部断层扫描（CT），因为死亡率相对风险降低20%。然而，关于 最有可能从这种干预中受益的患者群体。癌前病变，如非典型 在胸部CT上被识别为结节的腺瘤性增生和早期肺腺癌， 与良性结节难以区分，这可能导致积极的诊断和治疗干预， 并可能对良性结节患者或延迟诊断的NSCLC患者造成伤害。更好的诊断 并且需要治疗靶点来检测和治疗癌前病变和早期非小细胞肺癌， 治愈是可能的。更好地理解从癌前病变到坦率地说， 恶性非小细胞肺癌是必要的，以更准确和及时的诊断， 改善生存。 基因组不稳定是癌症的标志，DNA修复途径的改变与癌症的发生有关。 增加肺癌的风险。DNA修复蛋白，着色性干皮病C组（XPC）基因 在小鼠中，慢性吸烟降低了XPC的表达，在人类中， 肺腺癌我们的实验室已经发现XPC在保护免受发展方面的关键作用 吸烟和致癌物诱发的肺腺癌的发展。我们最近发现XPC 保护小鼠NTCU诱导的肺鳞状细胞癌的组织学进展。我们的初步 数据表明，XPC缺陷小鼠中致癌物诱导的肺癌的进展与以下因素相关： 增加拷贝基因组复杂性和更高的组织学分级。 基于这些发现，我们假设XPC减少DNA修复导致癌前病变， 具有特征性突变和表观遗传标记的病变，可预测进展为肺癌。我们 我建议从三个方面进行研究，使用癌前病变和早期NSCLC标本的人类样本 辅以我们完善的XC缺陷型尿烷肺腺癌进展模型。在Aim中 1，我们将确定XPC在从癌前病变向早期和晚期腺癌病理转变中的影响， 通过对从尿烷处理的XPC缺陷小鼠中分离的标本进行单细胞测序来分级， 并使用存档的基因组数据（NCBI基因表达综合数据库）确认人类中的正向突变 和体外机制研究。在目标2中，我们将确定免疫逃避对肺的机制影响， 在我们的小鼠肺腺癌进展模型中使用PD-L1抑制剂atezolizumab的致癌作用， 定义atezolizumab耐药肺腺癌的免疫基因型特征。最后， 在目标3中，我们将确定DNA修复对癌前病变中关键基因组和表观遗传变化的影响。 和早期人类肺鳞状细胞癌。DNA修复能力，由宿主细胞再活化决定 分析，将比较支气管上皮细胞异型增生消退或持续，和克隆基因组和 在发育不良样品中研究的转录组学差异，其进展/持续vs消退。研究 早期NSCLC发展中的机制和基因组不稳定性可能允许早期识别和新的 早期非小细胞肺癌的治疗靶点。