Biomarkers, mechanisms and modulation of oxidative stress associated risk factors in carcinogenesis

致癌过程中氧化应激相关危险因素的生物标志物、机制和调节

• 批准号: 10704632
• 负责人: Yun Rose Li
• 金额: $ 42.26万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-14 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10704632
• 关键词: Acute; Adverse event; Aging; Algorithms; Animal Model; Animals; Appointment; Architecture; Binding; Binding Sites; Biological; Biological Assay; Biological Markers; CCCTC-binding factor; Caloric Restriction; Cancer Biology; Cancer Patient; Carcinogen exposure; Carcinogens; Cause of Death; Cell Cycle Regulation; Cell Line; Cells; ChIP-seq; Chromatin; Chronic; Cities; Clinical; Clinical Data; Clonal Expansion; Colorectal; Colorectal Cancer; Colorectal Neoplasms; Computational Biology; Computational Technique; DNA Damage; DNA Repair; DNA Sequence Alteration; Data; Dedications; Defect; Developed Countries; Developing Countries; Development; Diet; Disease; Energy Intake; Epidemiology; Epigenetic Process; Exercise; Exposure to; Extramural Activities; Faculty; Fasting; Feces; Funding; Future; Genes; Genetic; Genomics; Growth; High School Student; Human; Incidence; Individual; Induced Mutation; Induction of Apoptosis; Inflammation; Inflammatory; Institution; Intake; Intermittent fasting; International; Joints; Journals; Laboratories; Lead; Leadership; Life Style; Link; Location; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Malignant neoplasm of prostate; Mathematics; Meat; Mediating; Medicine; Mentors; Mentorship; Metabolic; Molecular; Molecular Biology; Molecular Computations; Molecular Epidemiology; Mutagenesis; Mutagens; Mutation; Normal Cell; Normal tissue morphology; Obesity; Outcome; Oxidative Stress; Patients; Pattern; Peer Review; Pelvis; Peripheral Blood Mononuclear Cell; Personal Satisfaction; Phase I/II Trial; Physicians; Positioning Attribute; Postdoctoral Fellow; Predisposition; Probability; Process; Publications; Quality of life; Radiation; Radiation Oncology; Radiation therapy; Randomized; Reactive Oxygen Species; Rectal Cancer; Reporting; Research; Risk Factors; Safety; Science; Scientist; Smoking; Societies; Somatic Mutation; TP53 gene; Testing; Therapeutic; Therapeutic Index; Time; Tissues; Toxic effect; Translating; Treatment-related toxicity; Ultraviolet Rays; Unhealthy Diet; Urine; Urothelial Cell; Work; cancer cell; cancer genome; cancer initiation; cancer risk; carcinogenesis; career; career networking; chronic inflammatory disease; clinical translation; cohort; colon cancer patients; computerized tools; cytokine; dietary; driver mutation; epigenomics; experience; genome sequencing; improved; induced pluripotent stem cell; lifestyle data; lifestyle factors; modifiable risk; multidisciplinary; multiple omics; novel; obesity genetics; phase 3 study; pre-clinical; primary endpoint; professor; promoter; prospective; repaired; side effect; tool; transcriptome sequencing; tumor; tumorigenesis; whole genome

Abstract Cancer is the second most common cause of death in developed nations, and incidence is rising among developing nations. An estimated 70% of cancers are attributable to “modifiable” risk factors, including obesity, chronic inflammatory diseases, and poor diet, all of which have been associated with increased oxidative stress. These are not themselves “carcinogenetic”, but they are thought to act as “cancer promoters”, increasing the probability of developing cancer. With advances in whole genome sequencing and development of computational techniques to examine the cancer genome, we can now use mathematical profiling of somatic mutational profiles (termed mutational signatures) to identify potential causes underlying a given tumor (e.g., smoking versus UV light). It remains unclear, however, if there is a mutational signature that is a biomarker of cumulative lifetime exposure to reactive oxygen species (ROS)-mediated DNA damage and if this correlates with cancer-associated lifestyle factors. Here, we will utilize cutting-edge multi-omic profiling and molecular biology and computational tools to better understand the contribution/mechanism of oxidative stress as a cancer promoter. To examine the correlation of ROS mutational signature levels and inflammation-related cancer risk factors, we will perform whole genome sequencing and mutational signature analysis of a large cohort of colorectal tumors from patients with detailed, longitudinally collected lifestyle data (e.g., smoking, caloric intake, red meat intake, exercise level, etc.) collected by the Molecular Epidemiology of Colorectal Cancer study. We will also evaluate whether accumulation of ROS-generated mutations is biased toward CTCF binding loci and whether chromosomal architecture is modified by exposure to carcinogens or cancer- associated processes, thereby mediating unique “epigenomic signatures”. These aims will also provide data that can be used in the development of two novel computational tools for the analysis of cancer driver mutational signatures and epigenomic signatures of carcinogen exposure. Finally, we will test the molecular and clinical benefit of intermittent fasting during daily radiation therapy based on the hypothesis that lifestyle factors could modulate susceptibility to ROS mutagenesis. Patient- reported quality of life and clinician-reported adverse events, as well as molecular assay for tissue-specific levels of ROS-associated DNA damage, will allow us to assess whether intermittent fasting can reduce normal tissue toxicity. Successful completion of the proposed research will provide a comprehensive examination of the epidemiology and mechanism of ROS-mediated DNA damage in human cancers and demonstrate the safety and potential efficacy of intermittent fasting as a clinically translatable and easily adaptable approach to reducing both acute and chronic side effects associated with radiotherapy.

摘要 癌症是发达国家的第二大常见死因， 发展中国家。据估计，70%的癌症可归因于“可改变的”风险因素，包括肥胖， 慢性炎症性疾病和不良饮食，所有这些都与氧化应激增加有关。 应力它们本身并不“致癌”，但它们被认为是“癌症促进剂”， 增加患癌症的可能性。随着全基因组测序和发展的进步 的计算技术来检查癌症基因组，我们现在可以使用数学分析的体细胞 突变谱（称为突变特征）以鉴定给定肿瘤的潜在原因（例如， 吸烟对紫外线）。然而，目前还不清楚是否存在一种突变特征，这是一种生物标志物， 累积暴露于活性氧（ROS）介导的DNA损伤，如果这与 与癌症相关的生活方式因素。在这里，我们将利用尖端的多组学分析和分子生物学技术， 生物学和计算工具，以更好地了解氧化应激的贡献/机制， 癌症促进剂 研究ROS突变特征水平与炎症相关癌症风险的相关性 因素，我们将进行全基因组测序和突变签名分析的一个大的队列， 来自具有详细的、纵向收集的生活方式数据的患者的结肠直肠肿瘤（例如，吸烟，热量 摄入量、红肉摄入量、运动水平等）由大肠癌分子流行病学研究所收集 study.我们还将评估ROS产生的突变的积累是否偏向CTCF 结合位点以及染色体结构是否因暴露于致癌物或癌症而改变- 相关的过程，从而介导独特的“表观基因组签名”。这些目标还将提供数据 这可以用于开发两种新的计算工具，用于分析癌症驱动因素。 致癌物暴露的突变特征和表观基因组特征。 最后，我们将测试在每日放射治疗期间间歇性禁食的分子和临床益处 基于生活方式因素可以调节对ROS诱变的易感性的假设。病人- 报告的生活质量和临床医生报告的不良事件，以及组织特异性 ROS相关的DNA损伤水平，将使我们能够评估间歇性禁食是否可以减少正常的 组织毒性成功完成拟议的研究将提供一个全面的审查， ROS介导的DNA损伤在人类癌症中的流行病学和机制，并证明 间歇性禁食作为一种临床上可翻译且易于适应的方法的安全性和潜在疗效， 减少与放射治疗相关的急性和慢性副作用。

项目成果

Moving the Needle Forward in Genomically-Guided Precision Radiation Treatment.

推动基因组引导精准放射治疗的发展。

• DOI: 10.3390/cancers15225314
• 发表时间: 2023-11-07
• 期刊: CANCERS
• 影响因子: 5.2
• 作者: Tam, Andrew;Mercier, Benjamin D.;Thomas, Reeny M.;Tizpa, Eemon;Wong, Irene G.;Shi, Juncong;Garg, Rishabh;Hampel, Heather;Gray, Stacy W.;Williams, Terence;Bazan, Jose G.;Li, Yun R.
• 通讯作者: Li, Yun R.