Colorectal Cancer Projects Overview
This document outlines two projects conducted by the GI Collaborative Group focused on detecting and monitoring colorectal cancer using plasma protein markers and ctDNA/aberrantly methylated DNA markers. Project 1 aims to develop a panel of plasma biomarkers for the detection of adenomas and CRC, while Project 2 evaluates established panels for CRC detection and recurrence monitoring. The projects involve testing hypotheses to improve sensitivity and specificity in diagnosing and monitoring CRC.
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GI Collaborative Group Colorectal Cancer Projects Ken Kinzler Rocky Schoen Sandy Markowitz Bill Grady Kishore Guda Paul Lampe Bob Bresalier
PROJECT 1: Plasma Protein AA or CRC Detection Markers Study 1 - Determine whether 6 specified plasma proteomic biomarkers developed by the GI collaborative and markers contributed by companies predict AA and/or CRC and compare the panel s performance to FIT. Aim 1. To define sensitivity and specificity of specified plasma biomarkers for the detection of AA and/or CRC with samples that had positive and negative FIT values. Aim 2. To develop a combination rule for the markers comparing it with FIT and testing whether it makes the 75% sensitivity and 70% specificity for CRCs indicated for GLNE10 usage. We will use the minimum number of markers necessary and test combinations with and without FIT to determine the most viable panel. If the performance is not sufficient, we will add/subtract other markers from the GI collaborative group to enhance performance. Future: If successful. we will test the fixed, combination rule using samples from GLNE10.
Samples Collected in Denmark from individuals undergoing CRC screening; age 50 - 74 years, with either a positive FIT* test (8,415 individuals) or a negative FIT test (5,112 individuals). 100 FIT-negative with no CRC diagnosed within 2 years post draw 100 FIT-positive no CRC by colonoscopy 100 FIT-positive advanced adenoma 100 FIT-positive CRC (25 stage I, 25 stage II, 25 stage III, 25 stage IV) 100 FIT-negative CRC (25 stage I, 25 stage II, 25 stage III, 25 stage IV) *SENSA FIT
Biomarker Candidates Galectin-3 ligand BAG4 IL6ST VWF EGFR CD44 The sialyl Lewis-A and X content for the latter two proteins Abbott assayed proteins Clinical Genomics methylated genes Volition America Nu.Q test
PROJECT 2: CRC Diagnostic and Recurrence Early Detection Markers GOAL: To evaluate established panels of ctDNA and aberrantly methylated DNA markers in a common, plasma-based reference set, under a uniform, structured protocol of collection and processing. STUDY AIMS Aim 1. Test the hypothesis that established panels of ctDNA and aberrantly methylated genes used together as a primary screening modality for detection of colorectal cancer will be more sensitive and specific than either panel of markers alone. We will test this hypothesis first in Stage III and IV CRC, then in Stage I and II CRC. Aim 2. Test the hypothesis that established panels of ctDNA levels and aberrantly methylated genes will be better for monitoring of CRC patients with regional metastatic disease (stage III) than either panel of markers alone.
PROJECT 2: CRC Diagnostic and Recurrence Early Detection Markers A. Samples: Plasma samples collected by UPMC (Rocky Schoen) and Case (S. Markowitz) in stage II-IV (R0) CRC patients and screening colonoscopy control subjects Study 1: Diagnostic test: Case vs. Control design Study 2: Stage III CRC recurrence detection marker: B. Markers: 1) Circulating mutant DNA (Kinzler) 2) Circulating methylated genes: Markowitz, Grady (CWRU, FHCRC): mVIM, mITGA4 Claus Anderson (Arhus) Larry Lapointe (Clinical Genomics] 3) Protein based markers (Lampe, Bresalier)
NEXT STEPS for PROJECTS 1 and 2 PROJECT 1: Serum/Plasma Diagnostic markers Validation/Verification in Danish Cohort PROJECT 2: Circulating DNA markers Assess candidate methylated DNA markers Clinical Genomics and Arhaus markers Methylated VIM and ITGA4 Cross-lab validation Obtain samples from cases and controls for diagnostic markers study Accrue serial plasma samples from stage III CRC patients
