Molecular epidemiology of Barretts esophagus and cancer

描述（由申请人提供）：在过去的三十年中，食道腺癌（AC）的发病率在大多数国家迅速增加，但其原因尚不清楚。AC通常发生在巴雷特食管（BE）。在人群水平上，对于BE和AC的环境和遗传原因，以及改变BE的自然史导致癌症进展的因素所知相对较少。在这项基于人群的研究中，我们的目标是量化与反流性食管炎（RE）、BE和AC的流行病学和遗传风险因素暴露相关的风险。在平行生物标本分析中，我们的目标是利用微阵列基因表达谱和组织阵列识别BE和AC的分子亚型。为了实现这些目标，我们将在3年期间从为目标人群服务的所有病理实验室中抽取经活检证实的RE [n=400]、BE [n=700]或AC [n=300]患者的代表性组，并将其与两组对照进行比较。将从强制性选民登记册中抽取一组具有代表性的人口对照[n=600]，并从病理实验室抽取一组生物合成阴性的组织对照[n=400]。病例和对照组将回答相同的问卷，重点关注胃肠道症状，药物暴露（特别是反流促进剂，非甾体抗炎药，COX-2抑制剂，激素），以及吸烟，酒精，幽门螺杆菌感染和癌症家族史。将收集参与者的血液样本，以确定与RE、be和AC易感性相关的基因型。从病例和组织对照中，我们将获得活检或手术组织标本，目的是确定be和AC分子亚型的患病率。将从一定比例的临床AC病例中获得新鲜组织[n=50-100]，用于通过微阵列基因表达谱发现基因。通过对表达谱数据的全面挖掘，我们将确定BE和AC不同亚型的诊断标记物，预测进展和/或治疗反应可能性的预后标记物，以及合理设计治疗BE和AC的药物靶点。候选基因将在所有病例和组织对照中使用组织阵列技术进行石蜡切片验证。然后将进行流行病学分析，比较主要疾病类别（RE、be、AC）之间的暴露风险，以及RE、be和AC的分子亚型。

DESCRIPTION (provided by applicant): The incidence of adenocarcinoma (AC) of the esophagus has increased rapidly in most countries during the past three decades, yet the reasons are not well understood. AC typically arises on a background of Barrett's esophagus (BE). At the population level, relatively little is known about the environmental and genetic causes of BE and AC, or about factors which modify the natural history of BE to cause progression to cancer. In this population-based study, we aim to quantify the risks associated with exposure to epidemiologic and genetic risk factors for reflux esophagitis (RE), BE and AC. In parallel biospecimen analyses, we aim to identify molecular subtypes of BE and AC using microarray gene expression profiling and tissue arrays. To accomplish these aims, we will sample representative groups of patients with biopsyproven RE [n=400], BE [n=700] or AC [n=300] from all pathology laboratories servicing the target populations during a 3 year period, and compare them with two groups of controls. A representative group of population controls [n=600] will be sampled from a compulsory electoral register, and a group of biopsynegative tissue controls [n=400] will be sampled from the pathology laboratories. Cases and controls will answer identical questionnaires, focusing on gastro-intestinal symptoms, exposure to medications (especially reflux promoters, NSAIDs, COX-2 inhibitors, hormones), as well as smoking, alcohol, infection with Helicobacter pylori and family history of cancer. Blood samples will be collected from participants to identify genotypes associated with predisposition to RE, BE and AC. From cases and tissue controls, we will obtain specimens of biopsy or surgical tissue with the aim of determining the prevalence of molecular subtypes of BE and AC. Fresh tissue will be available from a proportion of clinic-based AC cases [n=50-100] for gene discovery through microarray gene expression profiling. From comprehensive mining of the expression profiling data we will identify diagnostic markers for the different subtypes of BE and AC, prognostic markers that predict likelihood of progression and/or response to therapy, and targets for rational drug design to treat BE and AC. Candidate genes will be validated in the paraffin sections available for all cases and tissue controls using tissue array technology. Epidemiologic analyses will then be performed comparing risks of exposure among the major disease groupings (RE, BE, AC), as well as for the molecular subtypes of RE, BE and AC.