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Team Project

Preliminary Validation of Biomarkers for the Detection of Colorectal Adenomas (Team Project #1)

347
Brenner, DeanUniversity of Michigan
Brenner, DeanUniversity of Michigan
EVL, ITGA4 MGMT, EVL, ITGA4, and CDKN2A, 2) genes that are not subject to methylation in colon cancer: GSTP1, BRCA1, and CDH1, and 3) genes that undergo aging related methylation in the colon: ESR1, MYOD1, and N33 Getzenberg CCSA-2
Genomics
Hypermethylation
Proteomics
Glycomics
G.I. and Other Associated Cancers Research Group
1

1   AIMS We propose a GI Collaborative biomarker validation project with the goal of identifying those biomarkers developed by the GI collaborative that will predict the presence of advanced colorectal adenomas. Biomarkers from the diverse colon focused and pancreatic focused BDLs of the GI Collaborative will assay their biomarkers on sets of identical reference set samples. The GI Collaborative will also assess markers of tissue/serum-plasma and/or urine from other EDRN collaborative groups, i.e. urologic, breast, lung, in this reference set. The most promising biomarkers that meet required adenoma detection bars will be assayed in a second, blinded test set of biosamples from a separate group of subjects before being considered for inclusion in large, cross sectional biomarker validation project for the early detection of both colorectal adenocarcinomas and advanced adenomas. Aim 1 To define preliminary sensitivity, specificity, and their variance of biomarkers for the detection of advanced adenomas in a standardized, open labeled training biosample reference set. Aim 2 To select those biomarkers for the detection of advanced adenomas in the training set for additional validation in a standardized biosample reference test set using pre-set performance characteristics. Aim 3 To verify sensitivity, specificity, and their variance of biomarkers for the detection of advanced adenomas in a standardized, blinded test biosample reference set. Aim 4 To select biomarkers for the detection of advanced adenomas from the test set for inclusion in a large, cross sectional validation trial of biomarkers for the early detection of advanced adenomas. 2   BACKGROUND AND SIGNIFICANCE 2.1   Current State of the Art: Recommended Early Detection    Colorectal adenocarcinoma remains the most common fatal cancer among non-smokers in the United States. Its lifetime incidence is sufficiently high at 6%, or 1 in 18, to justify population screening. It is encouraging that both colorectal cancer incidence and mortality have decreased in the past decade, developments attributed at least in part to more effective screening and surveillance (1). Wide scale screening using fecal occult blood tests results in up to a 30% reduction in colorectal adenocarcinoma (CRC) mortality, but at the expense of many colonoscopies in patients without neoplasia (2-5). Colonoscopy, while examining the complete colon, requires a thorough bowel preparation and sedation, causes patient discomfort, has a significant cost and carries a small, but non-negligible risk of complications (6-11). Patient-friendly approaches are needed with the combined features of high accuracy for cancer, high grade dysplasia, and adenomas >1cm (advanced adenomas including any tubulovillous and villous adenomas) and broad acceptability to the general population, health care providers, and third party payers (12).

We propose a GI Collaborative biomarker validation project with the goal of identifying those biomarkers developed by the GI collaborative that will predict the presence of advanced colorectal adenomas. Biomarkers from the diverse colon focused and pancreatic focused BDLs of the GI Collaborative will assay their biomarkers on sets of identical reference set samples. The GI Collaborative will also assess markers of tissue/serum-plasma and/or urine from other EDRN collaborative groups, i.e. urologic, breast, lung, in this reference set. The most promising biomarkers that meet required adenoma detection bars will be assayed in a second, blinded test set of biosamples from a separate group of subjects before being considered for inclusion in large, cross sectional biomarker validation project for the early detection of both colorectal adenocarcinomas and advanced adenomas. Aim 1 To define preliminary sensitivity, specificity, and their variance of biomarkers for the detection of advanced adenomas in a standardized, open labeled training biosample reference set. Aim 2 To select those biomarkers for the detection of advanced adenomas in the training set for additional validation in a standardized biosample reference test set using pre-set performance characteristics. Aim 3 To verify sensitivity, specificity, and their variance of biomarkers for the detection of advanced adenomas in a standardized, blinded test biosample reference set. Aim 4 To select biomarkers for the detection of advanced adenomas from the test set for inclusion in a large, cross sectional validation trial of biomarkers for the early detection of advanced adenomas.
Markowitz Approach: Candidate aberrant methylated loci will be identified from RRBS analysis of tissues in the archive of the Case Medical Center. Real-time MS-PCR assays will be developed to quantitatively assay for these aberrant methylation events. Validation of these methylation events, their timing, and their selectivity for neoplasia, will be examined in tissue samples from the GLNE archive including normal mucosal biopsy from individuals with clean colonoscopies, normal mucosal biopsies from individuals with colon neoplasia (advanced adenomas or cancers), biopsies of non-advanced adenomas, biopsies of advanced adenomas, biopsies of early stage colon cancers, and biopsies of late stage colon cancers. Marker loci that show sensitivity and specificity for colon neoplasia at the independent tissue collections of the GLNE will be tested for their sensitivity and specificity for early and late neoplasia detection in body fluids including in fecal DNAs and in plasma samples. Grady Approach: Quantitative CpG methylation assessment with quantitative methylation specific PCR (qMSP or MethyLight). Lampe compare protein expression/activation in adenoma vs. normal colon mucosa via antibody array to discover diagnostic/prognostic biomarkers. The best diagnostic and prognostic markers will then be rescreened on a tissue microarrays. After triage, we will determine whether the surviving biomarkers are adenoma or stromal derived by analyzing its expression pattern. Getzenberg evaluate the potential of CKB IHC staining within the colon to serve as a marker for the development of colon cancer and perhaps at the onset of adenomas. The laboratory is now developing a sandwich ELISA to detect CCSA-2 in the serum and would propose to evaluate this marker

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 06/26/2014


Please click here to register for the 9th EDRN Scientific Workshop from September 8-10, 2014, in Bethesda, Maryland. The meeting registration page also has agendas and hotel reservation information.
Announcement 06/05/2014


Funding Opportunity Available

Both RFAs for Molecular and Cellular Characterization of Screen-Detected Lesions have been published.

RFA-CA-14-010.html

and

RFA-CA-14-011.html