Sequence variation in mtDNA and extreme survival in glioblastoma

mtDNA 的序列变异与胶质母细胞瘤的极端生存

• 批准号: 9307011
• 负责人: Kathleen M. Egan
• 金额: $ 24.99万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-11 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9307011
• 关键词: Aerobic; Age; Aging; Archives; Area; Automobile Driving; Brain; Brain Neoplasms; Cell Line; Cells; Circular DNA; Clinical Data; Complementarity Determining Regions; DNA; DNA Damage; Data; Dependency; Development; Diagnosis; Disease; Dose; Drug resistance; Elements; Energy Metabolism; Enrollment; Eukaryotic Cell; Evaluation; Excision; Fermentation; Freezing; Frequencies; Gender; Gene Frequency; Genes; Genome; Germ Lines; Glioblastoma; Glioma; Glycolysis; Grant; Haplogroup; Heterogeneity; Human; Human Genome; Individual; Inherited; Institution; Investigation; Link; Malignant Glioma; Malignant Neoplasms; Minor; Mitochondria; Mitochondrial DNA; Modernization; Mutation; Neurodegenerative Disorders; Nucleotides; Operative Surgical Procedures; Oral; Organelles; Oxidative Phosphorylation; Pathogenicity; Pathway interactions; Patient-Focused Outcomes; Patients; Play; Population; Primary Neoplasm; Proteins; Radiation; Reactive Oxygen Species; Reporting; Research; Resistance; Resources; Role; Sampling; Somatic Mutation; Source; Survivors; Tissues; Translating; Translations; Treatment Efficacy; Tumor Tissue; Variant; Vital Status; Warburg Effect; base; biomedical referral center; cancer risk; chemotherapy; cohort; cost effective; digital; enzyme activity; epidemiology study; functional group; improved; insight; interest; mitochondrial genome; new therapeutic target; next generation sequencing; novel therapeutics; standard of care; temozolomide; therapeutic target; treatment response; tumor; tumor DNA; tumor progression; tumorigenesis

ABSTRACT Glioblastoma (GBM) is among the most lethal human malignancies. Median survival is a dismal 12-15 months in spite of aggressive treatment with surgery, radiation and concurrent temozolomide. New avenues are urgently needed for development of effective therapeutics. An emerging area of interest in cancer is the role of the mitochondria, cellular organelles which provide most of the energy needs of the body via oxidative phosphorylation (OXPHOS). Mitochondria possess an independent circular 16.5KB genome (mtDNA) that is an essential, and often overlooked, cytoplasmic element of the human genome. mtDNA encodes proteins critical to OXPHOS and is highly polymorphic in human populations and also subject to somatic variation. A growing body of evidence indicates that ancient and recent germline mtDNA variants and the burden of somatic alterations in mtDNA may play important roles in cancer risk and progression. In glioma, recent evidence points to OXPHOS enzyme activity and tissue mtDNA content playing a role in drug resistance and tumor grade. In this R21, we propose to carry out the first comprehensive investigation of germline and somatic mtDNA variation in GBM survival. The project is based on a unique resource of germline and tumor DNA from large numbers of GBM patients for whom uniform tumor and treatment data, and vital status are available. Germline mtDNA sequence will be determined using high-throughput next-generation sequencing of oral DNA samples. We will investigate whether germline variants distinguish infrequent `extreme survivors' (ES) of 3 years or longer from average survivors (AS) of 15 months or less (150 ES versus 450 AS matched for age and treatment). Mitochondrial haplogroups, common individual variants, as well as rare and singleton variants considered in aggregate within genes and functional pathways, will all be examined for association with patient outcome. We will then investigate, in exploratory analysis, whether somatic variants in tumor mtDNA contribute to patient survival (120 GBM patients with paired germline and fresh frozen primary tumor). Somatic variants will be determined by sequencing native tumor mtDNA employing high depth of coverage to capture low frequency variants within individuals. Structural and single nucleotide variants will be considered by class, total burden and predicted pathogenicity for association with patient outcome. The proposal is responsive to “Provocative Question 5” from the NCI eg: “ How does mitochondrial heterogeneity influence tumorigenesis or progression?” (http://grants.nih.gov/grants/guide/rfa-files/RFA-CA-15-009.html). Results will contribute new insight on questions surrounding the role of the mitochondrial genome in driving GBM and may point to novel therapeutic strategies that target mitochondrial function.

抽象的 胶质母细胞瘤（GBM）是最致命的人类恶性肿瘤之一。中位生存是一个令人沮丧的12-15个月 尽管手术，辐射和并发替莫唑胺都进行了积极的治疗。新途径是 迫切需要开发有效的治疗。癌症感兴趣的新兴领域是 线粒体，细胞器，可通过氧化提供人体的大部分能量需求 磷酸化（OXPHOS）。线粒体具有独立的圆形16.5kb基因组（mtDNA），即 人类基因组的必不可少且经常被忽略的细胞质元素。 mtDNA编码蛋白质 对Oxphos至关重要，在人群中是高度多态性的，并且也会受到躯体变异的影响。一个 越来越多的证据表明，古代和最近的种系mtDNA变体以及燃烧的燃烧 mtDNA的体细胞改变可能在癌症风险和进展中起重要作用。在神经胶质瘤中，最近 有证据表明OXPHOS酶活性和组织mtDNA含量在耐药性和 肿瘤等级。在此R21中，我们建议对种系和躯体进行首次全面调查 GBM存活中的mtDNA变异。该项目基于生殖线和肿瘤DNA的独特资源。 大量的GBM患者可为肿瘤和治疗数据均匀的GBM患者提供。 种系MTDNA序列将使用口服DNA的高通量下一代测序确定 样品。我们将调查生殖变体是否区分3个不频繁的“极端生存”（ES）3 年份或更长时间的平均存活率（AS）15个月或更少（150 ES与450年龄相匹配的450个 治疗）。线粒体单倍率，常见的个体变体以及稀有和单胎变体 在基因和功能途径中汇总考虑，将全部检查与患者的关联 结果。然后，我们将在探索性分析中调查肿瘤mtDNA中的体细胞变体是否有助于 给患者生存期（120名GBM配对种系和新鲜冷冻原发性肿瘤的患者）。躯体变体 将通过对天然肿瘤MTDNA进行测序，该肿瘤使用高覆盖范围捕获低 个体内部的频率变体。结构和单核苷酸变体将按班级考虑，总计 负担和预测与患者结局相关的致病性。该提议对 NCI的“挑衅性问题5”：“ 线粒体异质性如何影响肿瘤发生或 进步？” （http://grants.nih.gov/grants/guide/rfa-files/rfa-ca-15-009.html）。结果将有助于新 洞悉围绕线粒体基因组在驱动GBM中的作用的问题，并可能指向新颖 针对线粒体功能的治疗策略。