||5U01CA262678-02 Interpret this number
||Vanderbilt University Medical Center
||Searching the Blood Metabolome to Identify Risk Biomarkers for Biliary Tract Cancer
Biliary tract cancer (BTC), which includes cancers of the gallbladder and bile ducts, is the second most
common primary hepatobiliary cancer worldwide. BTC is highly fatal, with ~90% of its patients dying within five
years after diagnosis. A better understanding of the etiology of BTC is critical for designing cost-effective
prevention strategies to reduce the morbidity and mortality of this fatal cancer. The biliary tract plays a central
role in the metabolism and absorption of fat-soluble endogenous and exogenous compounds and in the
maintenance of normal liver functions. Many known risk factors for BTC are related to metabolic disturbance,
suggesting a significant role of metabolic perturbance in BTC pathogenesis. Thus, a systematic investigation of
circulating metabolites could provide valuable information regarding biomarkers for BTC risk and biological
mechanisms of BTC pathogenesis. Herein, we propose a well-powered, multi-ancestry study, using resources
from 17 large prospective cohort studies around the world and five large genetic consortia/studies of BTC, to
identify and validate metabolomic biomarkers for BTC risk. In Aim 1, we propose to analyze blood samples
collected prior to any cancer diagnosis from 750 incident cases and 750 matched controls to systematically
search the blood metabolome to identify promising metabolite biomarkers for replication. In Aim 2, we will use
genetic variants associated with circulating metabolites and data from large genome-wide association studies
(GWAS) of BTC to search for additional promising metabolite biomarkers for replication. In Aim 3, we will
quantify 50 promising metabolites selected from Aims 1 and 2 and evaluate their associations with risk of BTC
overall, and by its subsites, in an independent sample of nearly 2000 cases and their matched controls. Finally,
in Aim 4, we will build risk prediction models for BTC using metabolite biomarkers, genetic risk variants and
traditional risk factors. This is the first large study ever conducted to systematically search the blood
metabolome to identify risk biomarkers for BTC, and the first study to integrate metabolomic and genomic data
in BTC biomarker research. Including multi-ancestry populations will allow us to cross-validate research
findings and identify potential racial differences in biomarker associations. This study will provide substantial
novel data to improve the understanding of BTC etiology and identify biomarkers for BTC risk assessment.
Temporal trends of stages and survival of biliary tract cancers in the United States and associations with demographic factors.
, Mumma M.
, Zheng W.
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2023-08-22; , .