PQ 5 Exploring whole mitochondrial genome of screen detected pre-neoplastic lung lesions by novel approaches

PQ 5 通过新方法探索屏幕检测肿瘤前肺部病变的整个线粒体基因组

• 批准号: 9759813
• 负责人: Mohammad Obaidul Hoque
• 金额: $ 36.39万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-13 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9759813
• 关键词: Address; Adenocarcinoma; Adenocarcinoma In Situ; Aggressive behavior; Area; Atypical adenomatous hyperplasia; Biologic Development; Biological Assay; Biological Markers; Blood; Clinical; Clinical Sensitivity; Cytology; DNA; DNA Sequence Alteration; DNA copy number; Development; Diagnosis; Disease; Event; Frequencies; Future; Glandular Neoplasms; Heterogeneity; Histologic; Human; Lead; Lesion; Lung; Lung Adenocarcinoma; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Mitochondria; Mitochondrial DNA; Monitor; Mutation; Non-Invasive Lesion; Nuclear; Pathogenesis; Pathway interactions; Patients; Pattern; Performance; Phenotype; Plasma; Process; Resected; Respiratory Chain; Role; Sampling; Series; Solid Neoplasm; Somatic Mutation; Spiral Computed Tomography; Technology; Testing; The Cancer Genome Atlas; Training; Validation; base; cancer risk; carcinogenesis; circulating DNA; cohort; comparative; computed tomography screening; cost effective; digital; follow-up; histological specimens; insight; lung cancer screening; lung carcinogenesis; lung tumorigenesis; minimally invasive; mitochondrial DNA mutation; mitochondrial genome; molecular marker; neoplastic; next generation sequencing; novel; novel strategies; peripheral blood; pneumocyte; repaired; screening; tumor progression; tumorigenic

Project Summary: The human mitochondrial genome (MG) is prone to genetic alterations, which lead to somatic mutations, changes in mitochondrial DNA (mtDNA) copy number and altered expression of respiratory chain subunits. This is in part due to the fact that mtDNA has a limited ability to repair itself when it is damaged. Although a buildup of somatic mutations in mtDNA has been associated with increased cancer risk, the role of mtDNA alterations in malignant transformation of lung adenocarcinoma (LA) has not been addressed. Therefore, a clear understanding of changes in mtDNA along the pathway of lung tumorigenesis is critical for identifying molecular biomarkers related to carcinogenesis and tumor progression. Like all solid tumors, LA is thought to be initiated and to progress through a series of genetic alterations, including changes in mtDNA. Lungs resected for primary adenocarcinomas often harbor minute discrete foci of cytologically atypical pneumocyte proliferations designated as atypical adenomatous hyperplasia (AAH). Evidence suggests that AAH represents an initial step in the progression to adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and ultimately fully invasive adenocarcinoma. To delineate mitochondrial clonal heterogeneity as a function of tumor progression we will use novel high- throughput-PCR-based enrichment technology combined with next generation sequencing (NGS) to assess mtDNA alterations in samples isolated from AAH lesions collected from patients diagnosed with primary invasive adenocarcinoma or from different zones of histologic progression within the same AIS and MIA. In this way, we will gain a unique understanding of the mitochondrial heterogeneity of early lesions and the potential role of these clonal events in the progression of early glandular neoplasms. Next, we will sequence LA that were detected through spiral CT screening approach and interval cancers, which likely indicate their rapidly progressing phenotypes. Finally, we will validate mtDNA-derived mutations in paired plasma samples using a sensitive and robust digital PCR approach, which provides a novel opportunity for noninvasive early lung cancer detection. In summary, this proposal will identify mtDNA-derived somatic mutations along the progression of LA and will develop biomarkers that will allow us to better predict the fate of early lesions non-invasively.

项目摘要： 人线粒体基因组（MG）容易受到遗传改变，导致体细胞突变， 线粒体DNA（mtDNA）拷贝数的变化和呼吸链亚基的表达改变。这 部分原因是mtDNA在损坏时修复自身的能力有限。虽然是一个积累 mtDNA中的体细胞突变与癌症风险增加有关，MTDNA改变在 尚未解决肺腺癌（LA）的恶性转化。因此，清晰 了解沿肺肿瘤发生途径的mtDNA变化对于鉴定分子至关重要 与癌变和肿瘤进展有关的生物标志物。 像所有实体瘤一样，洛杉矶被认为是启动的，并通过一系列遗传变化进行进展， 包括mtDNA的变化。切除用于主要腺癌的肺通常具有分散焦点 在细胞学上非典型的肺细胞增殖，被指定为非典型腺瘤增生（AAH）。 有证据表明，AAH代表了对原位腺癌进展的第一步（AIS）， 微创腺癌（MIA）和最终完全浸润性腺癌。 为了描绘线粒体克隆异质性随肿瘤进展的函数，我们将使用新型高级 基于吞吐量PCR的富集技术与下一代测序（NGS）相结合以评估 从诊断为主要侵入性的患者中收集的AAH病变中分离出的样品中的mtDNA改变 腺癌或来自同一AIS和MIA内组织学进展的不同区域。这样，我们 将对早期病变的线粒体异质性和这些潜在作用有独特的理解 早期腺肿瘤进展的克隆事件。接下来，我们将序列的LA序列 通过螺旋CT筛选方法和间隔癌症，这可能表明它们的迅速发展 表型。最后，我们将使用敏感的和 强大的数字PCR方法，为无创的早期肺癌检测提供了新的机会。 总而言之，该提案将确定沿LA和LA和 将开发生物标志物，使我们能够更好地预测早期病变的命运。