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.

Public Health Relevance

This study aims to determine the clinical importance of a newly recognized sub-group of colorectal polyps, sessile serrated polyps. These polyps share specific characteristics with a subset of cancer;however, no official guidelines have yet been developed to consider the significance of these polyps in colorectal cancer screening practices. Therefore, we will follow-up people with sessile serrated polyps through normal care and medical records to determine if they should receive closer scrutiny aimed at preventing colorectal cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA168338-01A1
Application #
8452499
Study Section
Epidemiology of Cancer Study Section (EPIC)
Program Officer
Elena, Joanne W
Project Start
2013-04-22
Project End
2017-03-31
Budget Start
2013-04-22
Budget End
2014-03-31
Support Year
1
Fiscal Year
2013
Total Cost
$668,122
Indirect Cost
$139,494
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109