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

摘要 胃癌是全球最常见和最致命的癌症之一，占全球新发癌症的100多万。 2018年癌症诊断和78.3万人死亡。幽门螺杆菌(H.Pylori)感染是最重要的 非贲门部胃癌的危险因素和必备因素。同时针对的是高危人群 感染幽门螺杆菌似乎是一种引人注目的胃癌筛查和预防策略，具有重要意义 没有解决的问题是，只有1%到3%的幽门螺杆菌感染者会患上胃癌，这表明 仅基于幽门螺杆菌状况的这种策略是不够的，特别是在幽门螺杆菌相对 幽门螺杆菌感染率低。因此，发现和验证额外的生物标志物，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开发。这个 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 与癌症发生有关的生活方式因素。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和危险生物标记物 不同的癌症。然而，先前很少有研究集中于确定新的胃癌风险生物标记物。 使用代谢组学技术，特别是在预期设计环境中。我们最近进行了第一次 两个大型前瞻性队列中的嵌套式病例对照研究。我们的研究确定了5种相关代谢物 在多次比较校正后有患胃癌的风险和13个额外的代谢物候选 进一步调查。这些包括与维生素B12缺乏有关的代谢物，绿茶/咖啡的摄入量，以及 两种孕激素类固醇，代表了一些生物学上可信的机制，涉及到胃癌的病因。 在此，我们建议在一个新成立的国际财团内进行一项大规模的前瞻性调查 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记物，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、生活方式因素和饮食摄入量将针对1,600例突发事件和约2,000例进行统一 与来自8个预期队列的对照组进行匹配。拟议的研究将包括严格的两个阶段 筛选和验证亚洲人和白人患胃癌风险的循环代谢物生物标记物的设计(目的 1)。我们将进一步评估经过验证的生物标志物在亚裔美国人、非洲裔美国人、 以及未来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，我们将评估已识别的代谢物对关联的中介作用。 已知的危险因素与胃癌之间的关系，有助于了解相关的生物学机制 (目标3)。通过一系列精心设计的研究活动，对胃病的发病机制有了新的见解 癌症发生和未来风险评估工具开发的新生物标记物是可望的。

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.