AS195 - Candidate pathways in colorectal carcinogenesis: one-carbon metabolism and inflammation

Investigator Names and Contact Information

Cornelia Ulrich (neli.ulrich@hci.utah.edu)

Introduction/Intent

Introduction/Intent

Colorectal carcinogenesis is a multistage process and modifications in one-carbon metabolism and inflammation (both environmental and genetic) appear involved in the progression of this disease. Genetically defined groups of individuals may benefit from targeted interventions, such as an increase in nutritional intakes, or use of NSAIDs. However, no prospective studies of sufficient sample size have comprehensively assessed genetic variability in these pathways and interactions with appropriate environmental factors. Preliminary data show that vitamin B6 and B12 status are relevant for inflammatory conditions, yet no studies to date have combined analyses on both one-carbon metabolism and inflammation. As part of an ancillary study within the WHI Observational Cohort, we propose to investigate these two interrelated biologic pathways of demonstrated relevance to colorectal carcinogenesis. We propose to explore both genetic variability (e.g., polymorphisms with demonstrated functional relevance) and relevant biomarkers, and their associations with colorectal cancer. A nested case-control study is proposed, comprised of incident cases with colorectal cancer (CRC) risk and frequency-matched controls. Specific aims include to investigate CRC risk as related to 1) biomarkers relevant to one-carbon metabolism, including global DNA methylation; 2) biomarkers signaling the presence of inflammation; 3) polymorphisms in one-carbon metabolism; 4) polymorphisms in prostaglandin synthesis or pro-inflammatory cytokines.

The primary aims of this ancillary study will be to investigate two interrelated biologic pathways of demonstrated relevance to colorectal carcinogenesis. We plan to explore both genetic variability and relevant biomarkers, and their influence on colorectal cancer risk. The study population will consist of 988 cases and 988 controls.

Primary specific aims will be to investigate:

To investigate the association between biomarkers or polymorphisms relevant to one-carbon metabolism and colorectal cancer risk

To investigate the association between biomarkers or polymorphisms relevant to inflammatory processes and colorectal cancer risk

To investigate risk associated with specific genetic polymorphisms in one-carbon metabolism and variation in nutritional status of vitamins B6, B12 and folate (gene-nutrient interactions)

To investigate risk associated with genetic variation in prostaglandin synthesis or proinflammatory cytokines and variation in use of non-steroidal anti-inflammatory drugs (NSAIDs)

Secondary specific aims will be to investigate:

Associations between the above mentioned genetic variants and biomarkers in the respective biologic pathway

Associations between vitamin B6, B12, or folate status and inflammation markers (CRP. IL-6, IL-8, SAA, sICAM1, sVCAM1, VEGF-A and VEGF-D)

The combined effects of multiple genetic polymorphisms within one biologic pathway on relevant biomarkers and colorectal cancer risk

Results/Findings

Some of the publications related to this ancillary study are: 530, 1181, 1226.

For a complete, up-to-date list of WHI papers related to this ancillary study, please use the searchable Bibliography section of this website. To search for papers by study number, access the Simple Search, and enter the study number in the “Related Studies” field.