Prospective metabolomics investigation of gastric cancer risk in African Americans and European Whites with a low socioeconomic status

社会经济地位较低的非裔美国人和欧洲白人胃癌风险的前瞻性代谢组学调查

• 批准号: 10912190
• 负责人: Xiang Shu
• 金额: $ 30万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-22 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10912190
• 关键词: Accounting; African American; African American population; American; Antibodies; Antigens; Asian; Asian Americans; Asian population; Assessment tool; Biological; Biological Markers; Blood; Body mass index; Cancer Etiology; Cancer Patient; Cancer and Nutrition; Cessation of life; Chimeric Proteins; Coffee; Cohort Studies; Communities; Cytotoxin; Data; Development; Diagnosis; Diagnostic; Dietary intake; East Asian; Environmental Risk Factor; Etiology; European; Evaluation; Exposure to; Funding; Future; Goals; Green tea; Health; Helicobacter Infections; Helicobacter pylori; Hispanic; Hispanic Populations; Human; Individual; Infrastructure; Intake; International; Investigation; Latino; Latino Population; Low Prevalence; Malignant Neoplasms; Mediating; Mediation; Mexican Americans; Minority Groups; Neoplasm Metastasis; Nested Case-Control Study; Outcome; Pathway interactions; Patients; Pilot Projects; Plasma; Play; Population; Population Heterogeneity; Prevention; Process; Processed Meats; Progestins; Prospective cohort; Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial; Publishing; Race; Reporting; Research Activity; Research Design; Resources; Rest; Risk; Risk Assessment; Risk Factors; Role; SEER Program; Sampling; Screening for Gastric Cancer; Series; Smoking; Steroids; Stomach; Techniques; Time; United States; Validation; Vegetables; Vitamin B 12 Deficiency; Women' s Health; Work; biomarker validation; cancer biomarkers; cancer diagnosis; cancer risk; carcinogenesis; case control; cohort; demographics; design; design verification; disorder prevention; draining lymph node; drinking; epidemiologic data; gastric cancer prevention; gastric carcinogenesis; high risk population; improved; innovation; insight; lifestyle factors; low socioeconomic status; male health; malignant stomach neoplasm; metabolome; metabolomics; multi-ethnic; novel; novel marker; population based; prospective; racial minority population; response; screening; sex; specific biomarkers; steroid hormone; stomach cardia; tool; tumor progression

ABSTRACT Gastric cancer is one of the most common and deadly cancers globally, accounting for over one million new cancer diagnoses and 783,000 deaths in 2018. Infection of Helicobacter pylori (H. pylori) is the most important risk factor and a necessary cause for non-cardia gastric cancer. While targeting high-risk populations who are infected with H. pylori seems a compelling strategy for gastric cancer screening and prevention, a significant concern not addressed is that only ~1 to 3% of the H. pylori infected individuals develop gastric cancer, indicating that such strategy based on H. pylori status alone is insufficient, particularly among populations with a relatively low prevalence of H. pylori infection. Thus, discovering and validating additional biomarkers, especially non- invasive ones, are needed to facilitate the development of novel risk assessment tools for gastric cancer. The human metabolome reflects endogenous responses and processes to exposures, including environmental and lifestyle factors that are related to carcinogenesis. The use of advanced metabolomics techniques in prospective population-based cohort studies have successfully identified both novel etiologic factors and risk biomarkers for different cancers. However, few prior studies have focused on identifying novel risk biomarkers for gastric cancer using metabolomics techniques, particularly in prospective design settings. We recently conducted the first nested case-control study within two large prospective cohorts. Our study identified 5 metabolites associated with risk of gastric cancer after correction for multiple comparisons and 13 additional metabolite candidates for further investigations. These include metabolites related to vitamin B12 deficiency, green tea/coffee intake, and two progestin steroids, representing a few biologically plausible mechanisms involved in gastric cancer etiology. Herein, we propose to conduct a large prospective investigation within a newly formed international consortium to validate these highly promising findings, as well as discovering novel risk biomarkers, using both untargeted and targeted metabolomics approaches. Pre-diagnostic plasma samples and epidemiologic data including demographics, lifestyle factors, and dietary intakes will be harmonized for >1,600 incident cases and about 2,000 matched controls from eight prospective cohorts. The proposed study will incorporate a rigorous two-stage design to screen and validate circulating metabolite biomarkers for gastric cancer risk in Asians and Whites (Aim 1). We will further assess the generalizability of the validated biomarkers in Asian Americans, African Americans, and Hispanics/Latinos as well as discover novel race-specific biomarkers in these populations for future investigation (Aim 2). Finally, we will assess mediating effects of the identified metabolites on the associations between known risk factors and gastric cancer to facilitate the understanding of involved biological mechanisms (Aim 3). Through a series of rigorously designed research activities, fresh insights into mechanism of gastric carcinogenesis and novel biomarkers for future development of risk assessment tools are expected.

摘要 胃癌是全球最常见和最致命的癌症之一， 2018年癌症诊断和783，000例死亡。幽门螺杆菌（Helicobacter pylori，H. pylori）是最重要的 是非贲门部胃癌的危险因素和必然原因。同时针对高危人群， 感染艾滋幽门螺杆菌似乎是胃癌筛查和预防的一个令人信服的策略， 没有解决的问题是，只有约1至3%的H。pylori感染者发生胃癌，表明 这种策略基于H.仅幽门螺杆菌状态是不够的，特别是在相对 H.幽门感染因此，发现和验证其他生物标志物，特别是非生物标志物， 侵袭性的，需要促进新的胃癌风险评估工具的发展。的 人体代谢组反映了对暴露的内源性反应和过程，包括环境和 生活方式因素与致癌作用有关。先进代谢组学技术在前瞻性研究中的应用 基于人群的队列研究已经成功地确定了新的病因因素和风险生物标志物， 不同的癌症然而，很少有先前的研究集中在确定新的胃癌风险生物标志物 使用代谢组学技术，特别是在前瞻性设计环境中。我们最近进行了第一次 两个大型前瞻性队列的巢式病例对照研究。我们的研究确定了5种代谢物， 多重比较校正后胃癌风险和13种额外的代谢物候选物， 进一步调查。这些包括与维生素B12缺乏相关的代谢物，绿色茶/咖啡摄入， 两种类固醇，代表了胃癌病因学中的一些生物学上合理的机制。 在此，我们建议在一个新成立的国际财团内进行一项大型前瞻性调查 为了验证这些非常有希望的发现，以及发现新的风险生物标志物，使用非靶向的 和靶向代谢组学方法。诊断前血浆样本和流行病学数据，包括 人口统计学、生活方式因素和饮食摄入量将在> 1，600例事件和约2，000例事件中得到协调。 来自8个前瞻性队列的匹配对照。拟议的研究将包括一个严格的两阶段 筛选和验证亚洲人和白人胃癌风险的循环代谢物生物标志物的设计（目的 1）。我们将进一步评估经验证的生物标志物在亚裔美国人、非裔美国人、 以及在这些人群中发现新的种族特异性生物标志物， 调查（目标2）。最后，我们将评估所鉴定的代谢物对相关性的介导作用。 已知危险因素与胃癌之间的关系，以促进对相关生物学机制的理解 (Aim 3）。通过一系列严格设计的研究活动，对胃粘膜损伤的机制有了新的认识， 致癌作用和新的生物标志物的风险评估工具的未来发展的预期。