A Cohort Study of Sessile Serrated Polyps and Subsequent Colorectal Neoplasia

描述（由申请人提供）：结直肠癌筛查指南目前侧重于晚期腺瘤性息肉的检测和切除。然而，最近的证据表明，另一组息肉，无蒂锯齿状息肉（SSP），作为结直肠癌的重要前体，也可能需要提高警惕。SSP以前被归类为增生性息肉（HP），病变通常被认为没有恶性潜力。现在，越来越多的人认为SSP属于结直肠癌的“锯齿状途径”。由该途径产生的肿瘤通常位于近端结肠，其特征在于具有CpG岛甲基化表型（CIMP），并且通常在BRAF中表现出突变。这项研究的长期目标是描述新的高危人群，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，以检查SSP的临床意义，解决了以下具体目标：1）确定与Hp和无息肉对照相比，SSP相关的后续结直肠肿瘤形成的风险; 2）评估与SSP相关的后续肿瘤形成的风险是否根据息肉特征而变化，如大小，近端位置和SSP的数量; 3）确定SSP和HP的分子特征（如BRAF突变和CIMP状态）与随后的结直肠肿瘤形成风险之间的关联。为了实现这些目标，我们提出了一个回顾性队列研究的7,800名成员的综合医疗服务系统，组健康（GH）。年龄在24-74岁之间的男性和女性，在1998-2007年接受过基线结肠镜检查并有HP临床诊断（N= 3，900），以及基线时无结直肠病理学的结肠镜检查患者对照组（N= 3，900）将有资格参加本研究。基线时临床诊断为HP的队列成员将接受标准病理学审查，该审查在我们先前的结直肠息肉研究中开发和验证，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数据 特征和群组成员人口统计学。与西部华盛顿监测、流行病学和最终结果癌症登记处和GH医疗记录（截至2013年1月1日）的联系将用于回顾性确定偶发性结直肠息肉和坦率的结直肠癌。对于目标3，我们将在基线时患有HP或SSP的患者中使用巢式病例对照方法，收集基线息肉组织，并使用TaqMan PCR和CIMP使用结直肠癌特异性MethyLight PCR面板（CACNA 1G，IGF 2，NEUROG 1，RUNX 3和SOCS 1）检测组织DNA的BRAF突变。这将是评价SSP相关结局的最大队列研究，也是首次评价BRAF突变和CIMP状态作为晚期肿瘤风险的潜在生物标志物的研究。我们的研究结果将具有巨大的公共卫生重要性，将提供数据，为临床试验的发展提供信息，并最终影响临床医生将锯齿状息肉患者分诊到不同的结直肠癌筛查方案的方式。

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.