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

描述(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一种主要癌症。大约每114名男性和女性中就有1人将被诊断为胃癌。幽门螺杆菌对胃的定植是导致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%的人患上了胃癌。有证据表明，幽门螺杆菌在癌症的发生中起到了一定的作用，但对胃癌前病变的定植效果很差。这些病变中幽门螺杆菌的丢失和胃酸分泌的障碍可能有助于幽门螺杆菌的定植 其他促进胃癌发生的细菌引起的胃部疾病。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 疾病一直与胃癌有关。循环中的口腔细菌抗体水平也与胃肠道癌症有关，如口腔消化道癌和胰腺癌。这些数据表明，口腔微生物群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群的假设 会影响患胃癌的风险。首先，我们将使用诊断前口腔清洁样本和未来上海妇女健康研究(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-均具有高血清幽门螺杆菌血清阳性率(在SWHS和SMHS中为90%，在非裔美国人中为89%，在SCCS中为69%)-进行第一次前瞻性病例对照研究，使用鸟枪式元基因组学分析200例胃癌病例和400名对照(目标1)。其次，使用来自120例胃肠化生和240例对照的胃镜人群病例对照研究的胃样本，我们将把胃微生物组的组成与胃肠化生联系起来，胃肠化生是胃癌癌前序列中倒数第二阶段的一种癌前病变(目标2)。第三，在一个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名对照，然后我们将测试来自AIMS 1和2的新发现的细菌标记物的抗体是否与胃癌有关(AIMS 3)。我们还将研究细菌标志物与不同菌株幽门螺杆菌在胃癌中的相互作用。这个 鉴于人们越来越多地关注微生物群与胃肠道癌症之间的联系，提出的研究是及时的。这些研究将提供补充和全面的数据，这些数据可能有助于了解胃癌的病因和流行病学，并有助于制定未来的胃癌干预措施和风险分层。

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 infection 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 loss 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.