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Coordinated Studies on Etiology of Colorectal Tumors: Study Update and Expansion

Principal Investigator
Name
Wen-Yi Huang
Degrees
-
Institution
NCI, DCEG, OEEB
Position Title
-
Email
About this CDAS Project
Study
PLCO (Learn more about this study)
Project ID
2007-0220
Initial CDAS Request Approval
Dec 20, 2007
Title
Coordinated Studies on Etiology of Colorectal Tumors: Study Update and Expansion
Summary
Colorectal adenoma is a recognized precursor to colorectal cancer. We are studying risk factors for these conditions in the PLCO Trial. We have published more than 20 reports on colorectal adenoma etiology and have several investigations ongoing, expanding to studies of colorectal cancer. With an expanded number of cases now available and with improvements in laboratory technology, we update here on the approach for current studies of single nucleotide polymorphisms (SNPs) in a priori putative disease pathways (Aim 1) and of SNPs identified from genome-wide association studies (GWAS) of cancer and related phenotypes (Aim 2). We also propose new investigations, using recently acquired pathology samples, to examine risk factor relationships with specific molecular sub-types of disease (Aim 3), and using peripheral blood samples, to examine genome-wide methylation patterns as disease risk factors (Aim 4).The expanded study includes 2000 colorectal adenoma, 900 colorectal cancer cases and a similar number of controls. This large size case series identified in a nonbiased fashion and the availability of detailed risk factor questionnaires and biologic samples make this a uniquely rich resource for the ongoing and proposed investigations. The hypotheses under study expand on our and other's work, focusing on metabolism and cell-signaling pathways, and include promising new research areas of risk associated with SNP variation in new gene regions, by GWAS, in key response element regulatory sites, and with global methylation patterns. With tumor cores for DNA-based studies and tissue microarrays (TMAs) from cores for protein expression, the study also allows for sub-specification of risk by tumor molecular sub-type, e.g., chromosomal, microsatellite, and immunohistochemical (IHC) changes. Study of genome-wide DNA hypomethylation allows us to relate epigenetic events with genomic instability and colorectal tumor risk. We expect that the study will significantly expand knowledge on colon tumor risk factors, with respect to premalignant and malignant disease. The project is being carried out by a team of epidemiologists, statisticians and laboratory scientists, with a productive track record in this field. It will take approximately two years to complete.
Aims

1. Evaluate risk associations for colorectal tumors for high-priority genes and SNPs (Table 1), including (1) a set of ~500 maximally informative tagging SNPs for antioxidant response elements1 and P53 response elements2;3, and (2) tagging SNPs of ~75 selected genes involved in tobacco and dietary-related metabolism, one-carbon metabolism, NSAIDs metabolism and target, Wnt/beta-catenin signaling, and angiogenesis, as a continuation of the approved Study 2006-128 (Colorectal study update and expansion, Hayes et al). 2. Evaluate risks for colorectal tumors in relation to high-priority genetic associations identified in GWAS studies (e.g., 8q24 risk variants, and potentially obesity-related genes) and other studies, as a continuation of the approved Study 2006-299 (GWAS of colorectal tumors, Zanke et al.) for rapid replication of potentially important findings. 3. Evaluate risk associations for colorectal cancer and adenoma, for environmental and genetic factors in relation to tumor sub-type, as determined from pathologic sample trait analysis. Proposed molecular markers are listed in Table 2. 4. Evaluate risks for colorectal tumors in relation to genome-wide (global) DNA hypomethylation status in peripheral blood.

Collaborators

ULRIKE (RIKI) PETERS, PHD, MPH (Fred Hutchinson Cancer Research Center)

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