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。已知的EA危险因素有吸烟、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。迫切需要提高我们对EA病因的认识，寻找预防该疾病的方法。根据我们初步病例对照研究的几条证据，我们假设口腔微生物群有助于食管腺癌的发展：i)食管癌患者的前肠微生物群发生了全球性的改变，其中口腔微生物群的变化最为明显；ii)口腔共生细菌能够激活或降解香烟烟雾中的致癌物；iii)在NIH-PLCO队列研究中，口腔微生物群对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导致局部（口腔）和下游（食道）的癌症发展。PLCO口腔预诊断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口腔预诊断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：i)我们评估了PLCO样品的质量，发现多年前收集的样品仍然含有口腔微生物组分析所需的足够的微生物遗传物质（见C2部分）。ii)我们比较了口腔、食道和胃中食道疾病的微生物组改变，发现最强的表型关联是在口腔（见C1部分）。Iii)使用在癌症诊断之前收集的样本使我们能够检查微生物组变化是否先于癌症发展，iv)在高质量队列中使用已经收集的样本以及饮食和人口统计信息使本研究具有成本效益。我们提出了一项前瞻性研究，利用NCI-PLCO试验和美国癌症协会癌症预防研究II （ACS-CPS II）收集的诊断前口腔细胞样本，来解决微生物组变化与EA发展之间的时间顺序和病因学关系。这将是一项嵌套病例对照研究，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展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、古生菌）（目标3）。利用这些信息，我们将构建一个综合生物标志物小组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维度，即微生物危险因素，我们对食管腺癌的病因学和最近激增的理解。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和低风险组，以更有效地筛查和早期发现EA。高危患者微生物组的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.