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Team Project

Biomarkers of Risk for Colorectal Neoplasia (Team Project #2)

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1.William Grady/Fred Hutchinson Cancer Center/University of Washington: Markers of Methylation 2.Sanford Markowitz/Ireland Cancer Center/Case Western Reserve: Vimentin and 15-PGDH 3.Robert Getzenberg/Johns Hopkins School of Medicine: Creatine Kinase B 4.Paul Lampe/Fred Hutchison Cancer Research Center: Proteomic Markers 5.Daniel C. Liebler: Vanderbilt University School of Medicine: Proteomic Markers
Genomics
Proteomics
G.I. and Other Associated Cancers Research Group
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Investigators in the colon section of EDRN have a mutual interest in developing markers that would identify individuals at increased risk for colon neoplasia. Identifying biomarkers of risk is a high priority, because markers would offer the promise of guiding or tailoring expensive interventions such as colonoscopy to the target population most likely to benefit. The goal of this project is to evaluate biomarkers in normal colonic mucosa to determine their relationship to the occurrence of short- and long-term colorectal neoplasia. Candidate markers have been proposed by participating investigators based on promising preliminary data. The purpose of this team project is to evaluate these markers in a common, tissue-based reference set, under a uniform, structured protocol. All markers will be evaluated in a similar, stepwise fashion. Step 1: To assess the reproducibility and variability of marker expression within individuals, marker expression will be evaluated in duplicate samples from the same region of the colon and in 3 different sites around the colon, the rectum, left and right colon. Step 2: To characterize the inter-subject variability in marker expression by disease phenotype, differences in marker expression in normal colonic mucosa between subjects with and without adenomatous polyps will be compared. Step 3: To examine the relationship between marker expression and long-term adenoma recurrence, marker expression will be compared among subjects with baseline adenomas who have a recurrence of adenomatous polyps compared to those who do not recur. The markers to be tested include methylated genes, 15-PGDH mRNA, creatine kinase B, and proteomic markers in tissue lysates evaluated by antibody array and via liquid chromatography-multiple reaction monitoring mass spectrometry. These efforts can potentially identify markers that stratify or delineate individuals who may benefit from chemoprevention or require more intensified surveillance regimens. By enhancing the evidence supporting a field effect of cancer risk and by characterizing the molecular events involved, these markers could assist in the rational allocation of colonoscopy resources, a priority in colorectal cancer screening and surveillance.

1.   Characterization of intra-subject reproducibility and variability: To assess the reproducibility and variability of marker expression within individuals, we will evaluate marker expression in duplicate samples from the same region of the colon and in 4 different sites around the colon, the rectum, left, transverse and right colon. 2.   Characterization of inter-subject variability in marker expression by disease phenotype: To characterize the inter-subject variability in marker expression by disease phenotype, we will compare marker expression in normal colonic mucosa between subjects with and without adenomatous polyps. 3.   Characterization of the relationship of marker expression and long-term adenoma recurrence: To examine the relationship between marker expression and long-term adenoma recurrence, we will compare marker expression among subjects with baseline adenomas who have a recurrence of adenomatous polyps compared to those who do not.
Analysis Plan: A mixed effects linear model will be used to estimate means and between-patient and within-segment variance parameters; location of biopsy will be considered a fixed effect, and patient a random effect. The within-segment variance is an estimator of assay reliability, while the difference in means between segments indicates how well rectal or distal colon values agree with transverse and proximal colon values. The between-patient variances can be used to calculate effect sizes used in the design of subsequent trials. The biopsy location effect is an indicator of the consistency of the biomarkers throughout the colon; because these are normal tissue, not adenoma, biopsies, significant variation between biopsy sites would have implications for sampling strategies, and could indicate non-specificity of the marker for adenoma. Using Monte Carlo simulation of the proposed design, we determined that, in 90% of the simulated trials, the estimated between-patient variance was within 70% of the true value, and the estimated within-segment variance was within 28% of its true value. The power to test the null hypothesis of no difference in means between segments was in excess of 80% if the effect size (difference between segment means divided by within-segment standard deviation) was 0.8 or greater.

There are currently no biomarkers annotated for this protocol.

No datasets are currently associated with this protocol.


News

The final report of the 2013 Cancer Biomarkers Bioinformatics Workshop is now available.

Announcement 03/06/2014

Thank you to everyone who helped make the 27th EDRN Steering Committee Meeting a success. We look forward to seeing everyone at the 9th EDRN Scientific Workshop from September 8-11, 2014 in Washington D.C.

Announcement