Oral microbiome in esophageal adenocarcinoma

描述（由申请人提供）：虽然大多数主要癌症的发病率似乎稳定或下降，但自20世纪70年代以来，美国食管腺癌（EA）的发病率增加了6倍，原因不明。EA的已知危险因素是吸烟、肥胖和反流性食管炎;然而，这些因素并不能完全解释这种新出现的公共卫生负担。因此，提高对EA病因的认识，寻找预防该病的方法是当务之急。我们假设口腔微生物组有助于食管腺癌的发展，这是基于我们初步病例对照研究的几条证据：i）在食管腺癌中存在前肠微生物组的整体改变，其中在口腔微生物组中发现最强的变化，ii）口腔细菌能够激活或降解香烟烟雾中的致癌物，和iii）口腔微生物组对NIH-PLCO群组中口腔癌的发展具有潜在的预测能力。这些数据表明，口腔微生物组的改变可能有助于局部（口腔）和下游（食管）的癌症发展。PLCO预诊断口腔细胞样本是下一步食管癌微生物组研究中不可或缺的资源，因为：这些PLCO预诊断口腔细胞样本是下一步食管癌微生物组研究中不可或缺的资源，因为：（一）我们对PLCO样本的质量进行了评估，发现多年前采集的样本仍然含有足够的口腔微生物组所需的微生物遗传物质貌相（见第C2节），ii）我们比较了口腔、食管和胃中食管疾病的微生物组变化，发现口腔中的表型相关性最强iii）在癌症诊断之前收集的样品的使用允许我们检查微生物组变化是否先于癌症发展，和iv）在该高质量队列中使用已经收集的样品和饮食以及人口统计学信息使得该研究具有成本效益。我们提出了一项前瞻性研究，以解决微生物组的变化和EA的发展之间的时间顺序和病因关系，使用NCI-PLCO试验和美国癌症协会癌症预防研究II（ACS-CPS II）中收集的诊断前颊细胞样本。这将是一项巢式病例对照研究，包括106例食管腺癌病例和212例对照。我们将确定与食管腺癌发生风险相关的细菌分类群（目标1）、细菌基因/途径（目标2）和非细菌微生物（病毒、真菌、真菌）（目标3）。利用这些信息，我们将构建一组综合生物标志物来预测食管腺癌的发展风险。从这项研究中获得的知识可以增加一个新的层面，即，微生物的危险因素，以我们了解病因和最近激增的食管腺癌。如果确定，这些诊断前微生物生物标志物可用于将高危受试者分为高风险组和低风险组，以更有效地筛查和早期检测EA。使高危患者的微生物组正常化可能成为预防食管腺癌的新手段。

DESCRIPTION (provided by applicant): While the incidence of most major cancers appear stable or declining, the incidence of esophageal adenocarcinoma (EA) has increased 6-fold in the U.S. since the 1970s for reasons unknown. Known risk factors for EA are cigarette smoking, obesity, and reflux esophagitis; however, these factors do not completely explain this emerging public health burden. It is urgent to improve our understanding of EA etiology and find out ways to prevent this disease. We hypothesize that the oral microbiome contributes to the development of esophageal adenocarcinoma based on several lines of evidence from our preliminary case control studies: i) there is a global alteration of foregut microbiome in esophageal adenocarcinoma with the strongest changes found in the oral microbiome, ii) commensal oral bacteria are capable of activating or degrading carcinogens in cigarette smoke, and iii) the oral microbiome has potential predictive power for development of oral cancer in the NIH-PLCO cohort. These data suggest that alterations of oral microbiome could contribute to cancer development locally (oral cavity) and downstream (esophagus). The PLCO pre-diagnostic buccal cell samples are an indispensable resource in the next step of esophageal cancer microbiome study because: These PLCO pre-diagnostic buccal cell samples are an indispensable resource in the next step of esophageal cancer microbiome study because: i) We have evaluated the quality of the PLCO samples and found that the samples collected years ago still contain sufficient microbial genetic materials needed for oral microbiome profiling (see section C2), ii) We have compared microbiome alterations in esophageal diseases in the mouth, esophagus, and stomach and found the strongest phenotype association was in the mouth (see section C1), iii) use of the samples collected prior to cancer diagnosis allows us to examine whether microbiome changes precede to cancer development, and iv) use of already collected samples and diet and demographic information in this high quality cohort makes this study cost efficient. We propose a prospective study to resolve the temporal order and etiological relationship between changes in microbiome and development of EA using pre-diagnostic buccal cell samples collected in the NCI-PLCO trial and American Cancer Society Cancer Prevention Study II (ACS-CPS II). This will be a nested case control study including 106 incident esophageal adenocarcinoma cases and 212 controls. We will identify bacterial taxa (Aim 1), bacterial genes/pathways (Aim 2), and non- bacterial microorganisms (viruses, fungi, Archaea) (Aim 3) associated with risk for development of esophageal adenocarcinoma. Using this information, we will construct a panel of integrated biomarkers to predict risk of development of esophageal adenocarcinoma. Knowledge gained from this study could add a new dimension, i.e., microbial risk factors, to our understanding of the etiology and recent surge of esophageal adenocarcinoma. If identified, these pre-diagnostic microbial biomarkers could be used to stratify at-risk subjects into high and low risk groups for more efficient screening and early detection of EA. Normalization of the microbiome in at-risk patients could become a new means for preventing esophageal adenocarcinoma.