Lipidomics and Metabolomic Profiles and Pancreatic Cancer Risk in Women s Health Initiative Participants
Abstract
Pancreatic cancer is among the most fatal cancers and its incidence is increasing in the United States and globally. Most pancreatic cancers are ductal adenocarcinomas. Smoking, being overweight, having diabetes or chronic pancreatitis, heavy alcohol use, and a family history of pancreatic cancer might increase pancreatic cancer risk. Although long-term diabetes is a risk factor for pancreatic cancer, diabetes can also occur as a consequence of pancreatic cancer. Our earlier studies in two cohorts have demonstrated the usefulness of metabolomic and lipidomic approach for identifying metabolic disruptions in pancreatic cancer and their systemic effects that were not previously appreciated, as well as identifying metabolites related to subclinical disease years prior to pancreatic cancer diagnosis. Limitations of these earlier studies include that diabetes was only ascertained on all participants only at baseline, most of the cases were male, smokers, and/or non-Hispanic white. The proposed study addresses the FY21 DOD Pancreatic Cancer Research Program Focus Area Understanding the relationship between metabolic disruptions in pancreatic cancer and their systemic effects, including diabetes. We propose a prospective metabolomic and lipidomic association study with pancreatic cancer risk using prediagnostic blood samples from the Women s Health Initiative Study (WHI) participants who developed pancreatic cancer years later and those who do not develop pancreatic cancer (540 matched case-control sets, including 102 African American). We hypothesize that unique metabolites, metabolomic profiles, and lipid species will be prospectively associated with incident pancreatic cancer including those related to subclinical disease and diabetes. The aims of the proposed study are (1) To identify metabolites and lipid species and their systemic effects associated with pancreatic cancer. This will be accomplished using a non-targeted approach, to identify new plasma metabolite and lipid species associated with pancreatic cancer. We also will conduct time stratified analyses of the top metabolites and lipid species to identify those associated with subclinical cancer. (2) To identify groups of metabolites associated with diabetes and examine their association with PDAC. This will be accomplished using metabolite data in Aim 1 and detailed annually with collected incident diabetes data from the WHI to conduct a secondary analysis to identify metabolites associated with diabetes as the outcome and test for differences by pancreatic cancer status. We will then conduct a targeted association study of the top identified metabolites that characterize diabetes with PDAC risk. The WHI results will be examined alone and combined with earlier metabolomic and lipidomic results, for a combined total of ~1,250 nested case-control sets across the three cohorts. Innovation and Impact: Pancreatic cancer is highly fatal with no curative treatment beyond surgery at early stages. The strengths of our proposed research include the prospective design with prediagnostic blood samples, the relatively large number of pancreatic cancer cases, and the multidisciplinary research team. The annual ascertainment of diabetes in the WHI is unique and will permit detailed interrogation of the metabolic disruptions and heterogeneity of diabetes associated with PDAC, which is currently not well understood. The study will also permit exploratory analyses in African Americans, a group that has higher pancreatic cancer incidence rates and is understudied. The results from the three cohorts will facilitate replication and an adequately powered study with potential for meaningful advancement in understanding the systemic biology and mechanisms of pancreatic carcinogenesis and prevention. Therefore, this research is novel, high risk, and innovative, and may be the foundation for future research. The impact of this research in the short-term is that in com
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2211019
Entities
People
- Rachael Solomon
Organizations
- National Cancer Institute
- United States Army