Multi-Omics Profiling of Per- and Polyfluoroalkyl Substances and Chemical Exposures in Relation to Bladder and Upper Tract Urothelial Cancer Risk

Principal Investigator

Name
Jongeun Rhee

Degrees
ScD, MS

Institution
Henry M. Jackson Foundation for the Advancement of Military Medicine (Center for Prostate Disease Research, Murtha Cancer Center Research Program)

Position Title
Assistant Professor

Email
jrhee@cpdr.org

About this CDAS Project

Study
MACS (Learn more about this study)

Project ID
2026-0140

Initial CDAS Request Approval
Aug 17, 2026

Title
Multi-Omics Profiling of Per- and Polyfluoroalkyl Substances and Chemical Exposures in Relation to Bladder and Upper Tract Urothelial Cancer Risk

Summary
Per- and polyfluoroalkyl substances (PFAS) are environmentally persistent pollutants detectable in the serum of most U.S. adults, with elevated exposures among military personnel due to widespread use in firefighting foams by the U.S. Department of War (DoW). In 2023, the International Agency for Research on Cancer (IARC) classified two PFAS compounds: perfluorooctanoic acid (PFOA) as a human carcinogen and perfluorooctane sulfonic acid (PFOS) as a possible human carcinogen. Given that PFAS accumulate in the kidney and are excreted primarily through urine, the entire urothelial tract can be exposed to high PFAS levels, raising concerns for genitourinary carcinogenesis. While prior epidemiologic findings have focused on kidney and testicular cancer, emerging studies suggest a possible increased risk of bladder cancer, particularly with PFOS. In addition, firefighting, a PFAS-exposed occupation, has been classified by IARC as a human carcinogen based on strong epidemiologic evidence for bladder cancer. However, studies directly measuring serum or plasma PFAS levels, considered best practice to measure body burden, in relation to bladder cancer risk remain scarce. To understand PFAS-related carcinogenicity, we previously conducted metabolomic investigations among ≥3,000 individuals and observed associations of PFOA and PFOS with sphingolipid pathway metabolites relevant to cancer development. However, few human studies have incorporated multi-omics data to elucidate biological mechanisms.

Bladder cancer is the fourth most common cancer among men in the U.S. Nearly 40% of patients experience recurrence, and roughly 10% of non-muscle-invasive bladder cancer (NMIBC) cases progress to muscle-invasive bladder cancer (MIBC), which has markedly reduced survival rates. Upper tract urothelial carcinoma (UTUC) is a relatively rare malignancy accounting for 5-10% for all urothelial cancers, yet it often presents at advanced stages with a worse prognosis. Identifying modifiable exposures can have a significant impact on morbidity and mortality for both cancers. Bladder cancer is considered an environmentally induced malignancy; cigarette smoking is the primary risk factor and some chemical exposures (e.g., benzene) have been associated with both NMIBC and MIBC. While UTUC shares histologic features with bladder cancer, its environmental etiology remains significantly understudied.

To fill this gap, we aim to conduct a case-control study of pre-diagnostic serum levels of PFAS and other chemicals in relation to bladder cancer and upper tract urothelial carcinoma, with individually matched controls. At the forefront in exposomics, our team advances untargeted high-resolution mass spectrometry (HRMS) profiling to detect >50,000 chemical signals, including ~60 individual PFAS and hundreds of exogenous chemicals. We will combine this exposure data with endogenous metabolomic and proteomic profiling to characterize mechanisms underlying bladder cancer and UTUC development.

Aims

Aim 1: To determine whether pre-diagnostic serum levels of PFAS and other chemical exposures are associated with risk of bladder cancer and UTUC. We hypothesize that higher serum levels of PFOS and other PFAS are associated with increased risk of bladder cancer and UTUC. As secondary objectives, we will (1) characterize the distribution of serum PFAS and other chemicals by military occupational factors; (2) examine associations with chemical mixtures (PFAS and novel chemicals); and (3) assess whether the associations vary by tumor characteristics, including stage and grade of disease.

Aim 2: To identify serum metabolites and proteins associated with PFAS and other chemicals exposures and evaluate their associations with risk of bladder cancer and UTUC. We hypothesize that the PFAS exposure is associated with coordinated alternations in serum metabolites and proteins—particularly in pathways related to lipid metabolism, oxidative stress, and immune regulation—and that these molecular signatures are associated with increased risk of developing bladder cancer and UTUC.

Collaborators

Jongeun Rhee (Henry M. Jackson Foundation for the Advancement of Military Medicine)
Stella Koutros (National Cancer Institute)
Mark Purdue (National Cancer Institute)
Nocholas Bateman (Henry M. Jackson Foundation for the Advancement of Military Medicine)
Douglas Walker (Emory University)