Wei Zheng

M.D., Ph.D.

Vanderbilt University Medical Center

Professor and Director, Vanderbilt Epidemiology Center

PLCO (Learn more about this study)

2019-0004

Jul 10, 2019

Metabolomic profiling and bilary tract cancer risk

Biliary tract cancer is a highly fatal malignancy. Owing to its nonspecific clinical symptoms and the challenges of early detection, most cases are diagnosed at an advanced stage. Identification of novel biomarkers for biliary tract cancer will help to improve risk prediction and gain new insights into the biology of this fatal cancer. We recently completed a pilot study and identified multiple metabolites associated with biliary tract cancer risk. Herein, we propose a large-scale study to systematically search for novel biomarkers. Because of a relatively low incidence of this cancer, we propose to establish a consortium to include cancer cases and controls from multiple cohort studies. To date, we have recruited ~10 cohorts and identified ~1300 cases with blood samples collected prior to the diagnosis of any cancer (except for non-melanoma skin cancer). We hope to include the PLCO in this project and expect that the PLCO will contribute ~72 cases to this consortium, bring the total number of cases to ~1500. Blood samples from these incident cancer cases and their controls (1 to 2 match) will be profiled for approximately 1000 metabolites, which will be analyzed for their associations with biliary tract cancer risk. We will evaluate inter-relationships of lifestyle and genetic factors and blood metabolites in the risk of biliary tract cancer. We believe that this proposed study should generate substantial new data to improve the understanding of the biology and etiology of this cancer and design cost-efficient strategies for cancer risk assessment.

1) To identify novel metabolic biomarkers for CRC risk. We will perform assays to profile circulating metabolites in ~1500 cases and 3000 controls using the DiscoveryHD4 platform offered by the Metabolon. We request 150ul of serum sample from each of the cancer cases and their matched controls from the PLCO study.

2) To perform mediation analyses to evaluate inter-relationships of known lifestyle risk factors, blood metabolites, and cancer risk. We will use the metabolomics data described in Aim 1 and exposure data collected in the parent cohort studies for these analyses. We request relevant exposure data obtained in the PLCO for all PLCO cases and controls included in Aim 1.

3) Perform a GWAS of blood metabolomics to better understand the inter-relationship of genetic factors, blood metabolites, and cancer risk in subjects included in Aims 1 and 2 and other sources. Most PLCO participants have been genotyped in previous studies and thus no genotyping assay is needed for our study. We will use PLCO existing genotyping data for association analyses of blood metabolites.