Foregut Microbiome and Risk of Gastric Intestinal Metaplasia, and Gastric Cancer Risk

 描述（由申请人提供）：前肠微生物组、胃肠化生和胃癌风险摘要胃癌是世界范围内的主要癌症。大约每114名男性和女性中就有1名被诊断为胃癌。H.幽门螺杆菌是胃癌的主要危险因素。然而，99%有感染史的人仍然没有症状，只有不到1%的人发展为胃癌。有证据表明H.幽门螺杆菌在癌症的发生中起作用，但在胃癌前病变中定植较差。H的丢失。幽门螺杆菌和酸分泌障碍在这些病变可能会促进殖民的 促进胃癌发生的其他细菌。然而，没有流行病学研究确定其他细菌因素可能在胃癌中发挥作用。口腔健康 与胃癌有关的病症。口腔细菌抗体的循环水平也与胃肠道癌症有关，如口腔消化癌和胰腺癌。这些数据表明，口腔微生物组可能在胃肠道维护中发挥关键作用。针对整个人类微生物组测序的高通量测序工作使得全面评估与胃癌相关的特定细菌分类群成为可能。在这个项目中，我们将测试前肠微生物组 影响胃癌风险。首先，我们将使用诊断前口腔清洗样本和前瞻性上海女性健康研究（SWHS）、上海男性健康研究（SMHS）和南方社区队列研究（SCCS）的独特资源，所有这些研究都具有高的H。pylori（SWHS和SMHS>90%，SCCS中非洲裔美国人89%，高加索人69%）-使用鸟枪宏基因组分析对200例胃癌病例和400例对照进行首次口腔微生物组和胃癌的前瞻性病例对照研究（目标1）。其次，使用来自一项基于内镜人群的病例对照研究的胃样本，其中包括120例胃肠道化生和240例对照，我们将胃微生物组的组成与胃肠道化生相关联，胃肠道化生是胃癌癌前序列中倒数第二阶段的癌前病变（目的2）。第三，在一项单独的大型前瞻性病例对照研究中，嵌套在相同的SWHS，SMHS和SCCS中，有700例病例和800例对照，我们将测试目标1和2中新鉴定的细菌标志物的抗体是否与胃癌相关（目标3）。我们还将研究细菌标记物与不同H.幽门螺杆菌在胃癌中的作用的 鉴于微生物组与胃肠道癌症之间的联系越来越受到关注，拟议的研究是及时的。这些研究将提供补充和全面的数据，可能有助于了解胃癌的病因学和流行病学，以及帮助制定未来的干预措施和胃癌的风险分层。

 DESCRIPTION (provided by applicant): Foregut Microbiome, Gastric Intestinal Metaplasia, and Gastric Cancer Risk Abstract Gastric cancer is a major cancer worldwide. Approximately 1 in 114 men and women will be diagnosed with gastric cancer. Colonization of the stomach by H. pylori is a major risk factor for gastric cancer. However, 99% of people with a history of infectio remain asymptomatic and only less than 1% develop gastric cancer. Evidence suggests that H. pylori plays a role in cancer initiation but colonizes gastric precancerous lesions poorly. The los of H. pylori and impairment of acid secretion in these lesions might facilitate colonization of the stomach by other bacteria that promote gastric carcinogenesis. However, no epidemiologic studies have identified other bacterial factors that may play a role in gastric cancer. Oral health conditions have been related to gastric cancer. Circulating levels of antibodies to oral bacteria have also been related to gastrointestinal cancers, such as orodigestive cancer and pancreatic cancer. These data suggest that the oral microbiome may play a critical role in gastrointestinal maintenance. High-throughput sequencing efforts directed toward sequencing the entire human microbiome have made it possible to comprehensively evaluate specific bacterial taxa that are related to gastric cancer. In this project, we will test the hypothesis that the foregut microbiome influences gastric cancer risk. First, we will use pre-diagnostic oral wash samples and unique resources of the prospective Shanghai Women's Health Study (SWHS), Shanghai Men's Health Study (SMHS), and Southern Community Cohort Study (SCCS)-all with a high seroprevalence of H. pylori (>90% in SWHS and SMHS, and 89% in African Americans and 69% in Caucasians in SCCS)-to conduct the first prospective case-control study of the oral microbiome and gastric cancer, using shotgun metagenomic analyses with 200 gastric cancer cases and 400 controls (Aim 1). Second, using gastric samples from an endoscopic population-based case-control study with 120 cases of gastric intestinal metaplasia and 240 controls, we will associate the composition of the gastric microbiome with gastric intestinal metaplasia, a precancerous lesion at the next-to-last stage of the preneoplastic sequence of gastric cancer (Aim 2). Third, in a separate large prospective case-control study nested in the same SWHS, SMHS, and SCCS with 700 cases and 800 controls, we will then test if antibodies of the newly-identified bacterial markers from Aims 1 and 2 are related to gastric cancer (Aim 3). We will also investigate the interaction between the bacterial markers and different strains of H. pylori in gastric cancer. The proposed study is timely, given the increasing attention on the link between the microbiome and gastrointestinal cancers. These studies will provide complementary and comprehensive data that may be useful to understand the etiology and epidemiology of gastric cancer, as well as to help the development of future interventions and risk stratifications for gastric cancer.