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Investigating pre-diagnostic blood proteomic profiles in relation to pancreatic ductal adenocarcinoma risk

Principal Investigator
Name
Ting Zhang
Degrees
Ph.D.
Institution
National Cancer Institute
Position Title
Postdoctoral Fellow
Email
About this CDAS Project
Study
PLCO (Learn more about this study)
Project ID
2025-0006
Initial CDAS Request Approval
Jun 12, 2025
Title
Investigating pre-diagnostic blood proteomic profiles in relation to pancreatic ductal adenocarcinoma risk
Summary
Pancreatic ductal adenocarcinoma (PDAC), the major pancreatic cancer, is highly fatal with a 5-year survival rate of only 6.6%. This high mortality is largely due to late-stage diagnoses, where curative treatment options are limited. PDAC etiology remains poorly understood, with only a few established modifiable risk factors (smoking, diabetes, adiposity) and 20 loci identified from genome-wide association studies. The circulating proteome presents a promising opportunity for understanding the etiology of PDAC, mechanisms underlying genetic and non-genetic risk factors, and non-invasive biomarker discovery, prevention, and identification of potential drug targets for PDAC. Our preliminary analyses from Mendelian randomization (MR) have identified genetic susceptibility to 130 plasma proteins that were associated with PDAC risk. Our metabolomic and lipidomic studies within PLCO and the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study have observed certain metabolites and lipidomic measures and metabolic pathways associated with PDAC risk. We propose expanding our preliminary studies by measuring plasma proteomic profiles by using the Olink Explore HT platform, in baseline samples from 491 cases and 491 controls (343 cases and 343 controls were part of a previous nested case-control study [EEMS-2012-0066 and EEMS-2016-0003] and 148 additional cases ascertained during the most recent follow-up to 2019 and matched controls) and single serial samples from 271 cases and matched controls in PLCO to examine the associations between plasma 5400 proteins and PDAC risk. We hypothesize that certain proteins will be associated with PDAC.
Aims

Primary aims:
1. To examine the associations between pre-diagnostic circulating proteomic profiles and PDAC.
2. To examine the associations between changes in protein levels over time and PDAC.
Secondary aims:
1. To examine the associations between identified pre-diagnostic PDAC-associated circulating proteins and metabolomic and lipidomic profiles previously measured and explore mediation of metabolites, lipid species, and fatty acids in the observed protein–PDAC association.
2. To examine associations between PDAC genetic and non-genetic risk factors (genetic susceptibility, smoking, diabetes, adiposity, alcohol) and proteomic profiles and explore mediation of proteins in observed association of these factors with PDAC.

Collaborators

Ting Zhang (National Cancer Institute)
Rachael Stolzenberg-Solomon (National Cancer Institute)
Steven C. Moore (National Cancer Institute)
Kai Yu (National Cancer Institute)