A Cohort Study of Sessile Serrated Polyps and Subsequent Colorectal Neoplasia

描述（申请人提供）：结直肠癌筛查指南目前侧重于晚期腺瘤性息肉的发现和切除。然而，最近的证据表明，另一组息肉，无梗锯齿状息肉（ssp），作为结直肠癌的重要前体，可能也需要提高警惕。ssp以前与增殖性息肉（HPs）分组，通常认为病变没有恶性潜能。现在，越来越多的人认为ssp属于结直肠癌的“锯齿状通路”。由该途径引起的肿瘤通常位于结肠近端，其特征是具有CpG岛甲基化表型（CIMP），并且经常在BRAF中表现出突变。本研究的长期目标是确定新的高危人群的特征，以提高结直肠癌筛查的有效性。为了实现这一目标，我们提出了一项研究来检验ssp的临床意义，以解决以下具体目标：1)相对于hp和无息肉对照，确定与ssp相关的后续结直肠肿瘤的风险；2)评估与ssp相关的后续瘤变风险是否根据息肉的特征（如大小、近端位置、ssp数量）而有所不同；3)确定ssp和HPs的分子特征，如braf突变和cimp状态与后续结直肠肿瘤发生风险的关系。为了实现这些目标，我们提出了一个回顾性队列研究7800名成员的综合医疗保健服务系统，群体健康（GH）。在1998-2007年间接受基线结肠镜检查并临床诊断为hp的24-74岁男性和女性（N= 3900）以及基线时无结直肠病理的结肠镜检查患者的对照组（N= 3900）将符合本研究的条件。基线时临床诊断为hp的队列成员将接受标准病理检查，该检查在我们之前的结肠直肠息肉研究中开发并验证，以确认诊断并根据标准组织学标准区分ssp。将提取医疗记录以收集基线息肉的数据

DESCRIPTION (provided by applicant): Colorectal cancer screening guidelines currently focus on the detection and removal of advanced adenomatous polyps. However, recent evidence implicates an additional group of polyps, sessile serrated polyps (SSPs), as important precursors to colorectal cancer that may also warrant increased vigilance. SSPs were previously grouped with hyperplastic polyps (HPs), lesions routinely believed to have no malignant potential. Now, there is growing consensus that SSPs belong on the "serrated pathway" to colorectal cancer. Tumors resulting from this pathway are usually located in the proximal colon, characterized as having a CpG island methylator phenotype (CIMP), and often exhibit mutations in BRAF. The long term goal of this study is to characterize new high-risk groups to improve the effectiveness of colorectal cancer screening. In working towards this goal, we propose a study to examine the clinical significance of SSPs that addresses the following specific aims: 1) determine the risk of subsequent colorectal neoplasia associated with SSPs relative to HPs and polyp-free controls; 2) evaluate whether the risk of subsequent neoplasia associated with SSPs varies according to polyp characteristics, such as size, proximal location, and the number of SSPs; 3) determine the association between molecular characteristics of SSPs and HPs, such as BRAF-mutation and CIMP-status, and risk of subsequent colorectal neoplasia. To accomplish these aims, we propose a retrospective cohort study among 7,800 members of the integrated healthcare delivery system, Group Health (GH). Men and women, aged 24-74, who received a baseline colonoscopy from 1998-2007 and had a clinical diagnosis of HPs (N=3,900) and a comparison group of colonoscopy patients with no colorectal pathology at baseline (N=3,900) will be eligible for this study. Cohort members with clinically diagnosed HPs at baseline will undergo a standard pathology review, developed and validated in our prior studies of colorectal polyps, to confirm the diagnosis and to distinguish SSPs according to standard histological criteria. Medical records will be abstracted to gather data on baseline polyp characteristics and cohort member demographics. Linkage to the Western Washington Surveillance, Epidemiology, and End Results cancer registry and GH medical records through January 1, 2013 will be used to retrospectively ascertain incident colorectal polyps and frank colorectal carcinoma. For Aim 3, we will use a nested case-control approach among those with HPs or SSPs at baseline, collect baseline polyp tissue, and test tissue DNA for BRAF mutation using TaqMan PCR and CIMP using a colorectal cancer-specific MethyLight PCR panel (CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1). This will be the largest cohort study to evaluate outcomes associated with SSPs and the first to evaluate BRAF- mutation and CIMP-status as potential biomarkers for advanced neoplasia risk. Our study findings will have great public health importance, will provide data to inform clinical trial development, and ultimately affect the way clinicians triage individuals with serrated polyps to different colorectal cancer screening regimens.