Uncovering Roles of Metabolites in Colorectal Cancer Etiology

揭示代谢物在结直肠癌病因学中的作用

• 批准号: 10440348
• 负责人: Xiang Shu
• 金额: $ 24.93万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10440348
• 关键词: Affect; Asia; Asian; Asian population; Award; Biological; Biological Markers; Blood; Blood specimen; Body mass index; Branched-Chain Amino Acids; Cancer Biology; Cancer Etiology; Clinical; Cohort Studies; Collaborations; Colorectal; Colorectal Cancer; Communities; Data; Development; Diagnosis; Diagnostic; Dietary intake; Disease; Dyslipidemias; Energy Metabolism; Etiology; European; Framingham Heart Study; Genetic; Genetic Predisposition to Disease; Genotype; Goals; Healthy Eating; Homeostasis; Intake; Investigation; K-Series Research Career Programs; Knowledge; Life Style; Link; Liquid Chromatography; Malignant Neoplasms; Malignant neoplasm of pancreas; Measurement; Measures; Meat; Mediation; Mediator of activation protein; Mentors; Metabolic; Metabolic Diseases; Metabolism; Modeling; Molecular Epidemiology of Cancer; Molecular Genetics; Nested Case-Control Study; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Observational Study; Parents; Participant; Pathway interactions; Phase; Physical activity; Pilot Projects; Plasma; Play; Population Genetics; Predisposition; Prevention; Prospective Studies; Research; Research Personnel; Risk; Risk Assessment; Risk Factors; Role; Sample Size; Susceptibility Gene; Techniques; Time; Training; Translating; United States; Vegetables; Waist-Hip Ratio; Woman; base; cancer biomarkers; cancer diagnosis; cancer initiation; cancer risk; career; case control; colorectal cancer prevention; colorectal cancer risk; cost; cost efficient; density; design; genetic epidemiology; genetic predictors; genetic variant; genome wide association study; genome-wide; genomic locus; good diet; high throughput technology; improved; in silico; indexing; innovation; instrument; lifestyle factors; male health; meetings; metabolome; metabolomics; novel; novel marker; offspring; physical inactivity; potential biomarker; predictive modeling; prevent; prospective; public database; risk stratification; screening; tandem mass spectrometry; tool; tumor metabolism; tumor progression

PROJECT SUMMARY Metabolic perturbation or reprogramming is considered one of the hallmarks of cancer. Several common metabolic disorders, such as obesity, type 2 diabetes, and dyslipidemia, have been linked to colorectal cancer (CRC) risk. With the advances in the techniques of metabolomics, hundreds to thousands of metabolites can be systematically measured in an agnostic manner. For a well-designed prospective metabolomic study of cancer, the identification of novel risk-associated biomarkers will shed new lights on the cancer etiology and related biological pathways. Conventional studies evaluating metabolites are costly and may suffer from biases commonly encountered in the observational studies. It has been increasingly recognized that genetic factors play a significant role in determining the levels of many metabolites. Herein, I propose a cost-efficient approach to systematically evaluate the associations between plasma levels of metabolites and CRC risk. I also incorporate didactic training on molecular/genetic epidemiology, causal inference, cancer biology and metabolism, and population genetics in this application to accomplish my research and career goals described below. The proposed research is composed of four aims. In aim 1, I will build models to predict metabolite levels using existing metabolomics and high-density genotyping data from a public database and possible data generated at Vanderbilt. In aim 2, metabolites with satisfactory prediction accuracy and meeting other criteria will be evaluated in three large-scale CRC consortia with a combined sample size of ~80,900 cases and 115,000 controls to assess the associations of genetically predicted metabolite levels with CRC risk. In collaboration with other investigators during the R00 phase of this award, I will then conduct a nested case- control study to confirm up to ten metabolites identified from in silico analysis by direct measurement of these metabolites using pre-diagnosis plasma collected in three large cohort studies (aim 3). Finally, I will evaluate the potential mediation effects of metabolites for the associations between lifestyle factors including obesity (body mass index and waist-hip-ratio), physical activity, red meat intakes, vegetable intakes, healthy eating index and CRC risk (aim 4). This innovative study will, for the first time, systematically search for novel metabolite biomarkers for CRC risk using genetic instruments and validate the identified associations by direct measurement. In addition, this study will expand the understanding of underlying mechanisms causing CRC. The proposed career development award will help me building advanced knowledge of genetic and molecular epidemiology, cancer metabolism, and CRC etiology and risk assessment to transition to a successful independent investigator.

项目概要 代谢紊乱或重编程被认为是癌症的标志之一。几种常见的 肥胖、2型糖尿病和血脂异常等代谢紊乱与结直肠癌有关 （CRC）风险。随着代谢组学技术的进步，数百到数千种代谢物可以 以不可知的方式系统地测量。精心设计的前瞻性代谢组学研究 癌症，新的风险相关生物标志物的鉴定将为癌症病因学和 相关的生物学途径。评估代谢物的传统研究成本高昂且可能存在偏差 观察性研究中常见的情况。人们越来越认识到遗传因素 在确定许多代谢物的水平方面发挥着重要作用。在此，我提出一种经济高效的方法 系统评估血浆代谢物水平与结直肠癌风险之间的关联。我也 纳入分子/遗传流行病学、因果推理、癌症生物学和 新陈代谢和群体遗传学在此应用程序中实现我所描述的研究和职业目标 以下。拟议的研究由四个目标组成。在目标 1 中，我将建立模型来预测代谢物 使用来自公共数据库的现有代谢组学和高密度基因分型数据以及可能的数据 范德比尔特产生。在目标 2 中，代谢物具有令人满意的预测准确性并满足其他标准 将在三个大型 CRC 联盟中进行评估，样本量合计约为 80,900 例， 115,000 名对照者用于评估基因预测的代谢物水平与 CRC 风险之间的关联。在 在该奖项的 R00 阶段与其他调查人员合作，然后我将进行一个嵌套案例 - 对照研究通过直接测量来确认从计算机分析中鉴定出的多达十种代谢物 使用三项大型队列研究（目标 3）中收集的诊断前血浆进行代谢物分析。最后我来评价一下 代谢物对肥胖等生活方式因素之间关联的潜在中介作用 （体重指数和腰臀比）、身体活动、红肉摄入量、蔬菜摄入量、健康饮食 指数和 CRC 风险（目标 4）。这项创新研究将首次系统地寻找新颖的 使用遗传仪器分析 CRC 风险的代谢生物标志物，并通过直接验证确定的关联 测量。此外，这项研究将扩大对导致 CRC 的潜在机制的理解。 拟议的职业发展奖将帮助我建立遗传和分子方面的先进知识 流行病学、癌症代谢、结直肠癌病因学和风险评估，以成功过渡到 独立调查员。

项目成果

Mendelian randomization analyses of 23 known and suspected risk factors and biomarkers for breast cancer overall and by molecular subtypes.

• DOI: 10.1002/ijc.34026
• 发表时间: 2022-08-01
• 期刊: International journal of cancer
• 影响因子: 6.4

TBX1 functions as a putative oncogene of breast cancer through promoting cell cycle progression.

TBX1 通过促进细胞周期进展发挥乳腺癌假定癌基因的作用。

• DOI: 10.1093/carcin/bgab111
• 发表时间: 2022
• 期刊: Carcinogenesis
• 影响因子: 4.7
• 作者: Huang,Shuya;Shu,Xiang;Ping,Jie;Wu,Jie;Wang,Jifeng;Shidal,Chris;Guo,Xingyi;Bauer,JoshuaA;Long,Jirong;Shu,Xiao-Ou;Zheng,Wei;Cai,Qiuyin
• 通讯作者: Cai,Qiuyin

Prospective Proteomic Study Identifies Potential Circulating Protein Biomarkers for Colorectal Cancer Risk.

• DOI: 10.3390/cancers14133261
• 发表时间: 2022-07-03
• 期刊: Cancers
• 影响因子: 5.2

Evaluation of associations between genetically predicted circulating protein biomarkers and breast cancer risk.

评估基因预测的循环蛋白生物标志物与乳腺癌风险之间的关联。

• DOI: 10.1002/ijc.32542
• 发表时间: 2020
• 期刊: International journal of cancer
• 影响因子: 6.4
• 作者: Shu,Xiang;Bao,Jiandong;Wu,Lang;Long,Jirong;Shu,Xiao-Ou;Guo,Xingyi;Yang,Yaohua;Michailidou,Kyriaki;Bolla,ManjeetK;Wang,Qin;Dennis,Joe;Andrulis,IreneL;Castelao,JoseE;Dörk,Thilo;Gago-Dominguez,Manuela;García-Closas,Montserra
• 通讯作者: García-Closas,Montserra