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

基本信息

  • 批准号:
    10704632
  • 负责人:
  • 金额:
    $ 42.26万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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 在发达国家,癌症是第二大常见死因,而且 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,所有这些都与氧化增加有关 压力。这些物质本身并不“致癌”,但它们被认为是“癌症促进剂”, 增加罹患癌症的几率。随着全基因组测序和开发的进展 通过计算技术来检查癌症基因组,我们现在可以使用体细胞的数学图谱 突变特征(称为突变特征)以识别潜在的给定肿瘤的原因(例如, 吸烟与紫外线的对比)。然而,目前还不清楚是否存在突变特征,这是一种 终身累积暴露于活性氧(ROS)介导的DNA损伤,以及这是否与 与癌症相关的生活方式因素。在这里,我们将利用尖端的多基因组图谱和分子 生物学和计算工具以更好地理解氧化应激的贡献/机制 癌症促进者。 研究ROS突变信号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特征分析的一个大队列 来自具有详细的纵向收集的生活方式数据(例如,吸烟、卡路里)的患者的结直肠肿瘤 摄入量、红肉摄入量、运动量等)《结直肠癌分子流行病学》杂志收集 学习。我们还将评估ROS产生的突变的积累是否偏向于CTCF 以及染色体结构是否因接触致癌物或癌症而改变- 相关的过程,从而调节独特的“表观基因组签名”。这些目标还将提供数据 这可用于开发两种用于分析癌症驱动因素的新型计算工具 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突变的易感性的假设。病人- 报告的生活质量和临床医生报告的不良事件,以及组织特异性的分子检测 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降低正常 组织毒性。成功完成拟议的研究将全面审查 ROS介导的DNA损伤在人类癌症中的流行病学和机制 间歇禁食作为一种临床可翻译和易于适应的方法的安全性和潜在有效性 减少与放射治疗相关的急性和慢性副作用。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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:
  • 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.
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Yun Rose Li其他文献

Delayed definitive management of localized prostate cancer: what do we know?
局限性前列腺癌的延迟确定性治疗:我们知道什么?
  • DOI:
    10.1038/s41391-024-00876-2
  • 发表时间:
    2024-08-11
  • 期刊:
  • 影响因子:
    5.800
  • 作者:
    Osama Mohamad;Yun Rose Li;Felix Feng;Julian C. Hong;Anthony Wong;Zakaria El Kouzi;Mohamed Shelan;Thomas Zilli;Peter Carroll;Mack Roach
  • 通讯作者:
    Mack Roach
Experience from an Early Exposure Education Program in Radiation Oncology for High School and Undergraduate Students.
高中生和本科生放射肿瘤学早期暴露教育计划的经验。
  • DOI:
  • 发表时间:
    2024
  • 期刊:
  • 影响因子:
    3.3
  • 作者:
    Andrew Tam;C. Ladbury;Scott Glaser;Arya Amini;Yi;Yun Rose Li
  • 通讯作者:
    Yun Rose Li
Grade 5 Radiation Necrosis After Whole-Brain Radiation Therapy.
全脑放射治疗后 5 级放射性坏死。
  • DOI:
  • 发表时间:
    2024
  • 期刊:
  • 影响因子:
    3.3
  • 作者:
    Andrew Tam;Yun Rose Li;Terence Williams;Stephanie Yoon
  • 通讯作者:
    Stephanie Yoon
2012: Impact of Metabolic Syndrome on Testosterone Recovery after Stopping Androgen Deprivation Therapy
2012年:代谢综合征对停止雄激素剥夺治疗后睾丸激素恢复的影响
  • DOI:
    10.1016/s0167-8140(24)02304-1
  • 发表时间:
    2024-05-01
  • 期刊:
  • 影响因子:
    5.300
  • 作者:
    Andrew Tam;Qianhua Feng;Colton Ladbury;Juncong Ashley Shi;Nicholas Correnti;Stephanie Zheng;Jeffrey Wong;Savita Dandapani;Scott Glaser;Tanya Dorff;Yun Rose Li
  • 通讯作者:
    Yun Rose Li
Uncovering novel mutational signatures by emde novo/em extraction with SigProfilerExtractor
  • DOI:
    10.1016/j.xgen.2022.100179
  • 发表时间:
    2022-11-09
  • 期刊:
  • 影响因子:
    9.000
  • 作者:
    S.M. Ashiqul Islam;Marcos Díaz-Gay;Yang Wu;Mark Barnes;Raviteja Vangara;Erik N. Bergstrom;Yudou He;Mike Vella;Jingwei Wang;Jon W. Teague;Peter Clapham;Sarah Moody;Sergey Senkin;Yun Rose Li;Laura Riva;Tongwu Zhang;Andreas J. Gruber;Christopher D. Steele;Burçak Otlu;Azhar Khandekar;Ludmil B. Alexandrov
  • 通讯作者:
    Ludmil B. Alexandrov

Yun Rose Li的其他文献

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{{ truncateString('Yun Rose Li', 18)}}的其他基金

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:
    10481713
  • 财政年份:
    2022
  • 资助金额:
    $ 42.26万
  • 项目类别:
Examining the impact of the obesity-inflammation axis on cancer by genomic and transcriptomic profiling
通过基因组和转录组分析检查肥胖-炎症轴对癌症的影响
  • 批准号:
    9767517
  • 财政年份:
    2018
  • 资助金额:
    $ 42.26万
  • 项目类别:
Integrative Analysis of Genomic Risk Factors in Juvenile Idiopathic Arthritis
幼年特发性关节炎基因组危险因素的综合分析
  • 批准号:
    8717915
  • 财政年份:
    2014
  • 资助金额:
    $ 42.26万
  • 项目类别:
Integrative Analysis of Genomic Risk Factors in Juvenile Idiopathic Arthritis
幼年特发性关节炎基因组危险因素的综合分析
  • 批准号:
    8879958
  • 财政年份:
    2014
  • 资助金额:
    $ 42.26万
  • 项目类别:

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