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检测和切除。然而，最近的证据表明，另一组息肉，固着锯齿状息肉(SSP)，是结直肠癌的重要先兆，也可能需要提高警惕。SSP以前被归类为增生性息肉(HPS)，通常认为这种病变没有恶性潜能。现在，越来越多的人达成共识，认为SSP属于结直肠癌的“锯齿状路径”。由这一途径引起的肿瘤通常位于近端结肠，具有CpG岛甲基化表型(CIMP)的特征，并且经常在BRAF中表现出突变。这项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。为了达到这一目标，我们提议进行一项研究，以检验SSP的临床意义，以解决以下具体目标：1)确定与HPS和无息肉对照组相比，SSP相关的后续大肠肿瘤的风险；2)评估与SSP相关的后续肿瘤的风险是否因息肉特征而异，如大小、近端位置和SSP的数量；3)确定SSP和HPS的分子特征之间的关联，如BRAF突变和CIMP状态，以及后续大肠肿瘤的风险。为了实现这些目标，我们建议对综合医疗保健提供系统--团体健康(GH)的7800名成员进行一项回顾性队列研究。年龄24-74岁的男性和女性，在1998-2007年间接受了基线结肠镜检查，并有HPS的临床诊断(N=3,900)，以及对照组的结肠镜检查患者在基线没有结直肠病理(N=3,900)将有资格参加这项研究。临床诊断为HPS的队列成员将接受标准的病理回顾，该回顾是在我们先前的大肠息肉研究中发展和验证的，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有关基线息肉的数据 特征和队列成员人口统计。到2013年1月1日为止，将使用与西华盛顿监测、流行病学和最终结果癌症登记和生长激素医疗记录的联系来回顾确定发生的大肠息肉和直肠癌。对于目标3，我们将在基线为HPS或SSP的患者中使用嵌套病例对照方法，收集基线息肉组织，并使用TaqMan PCR和CIMP检测组织DNA中的BRAF突变，使用结直肠癌特异性的MethyLight PCR小组(CACNA1G、IGF2、NEUROG1、RUNX3和SOCS1)。这将是评估与SSP相关的结果的最大的队列研究，也是第一次评估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重大的公共卫生意义，将提供数据为临床试验发展提供信息，并最终影响临床医生将锯齿状息肉患者分流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.