Author ORCID Identifier

Date of Award

Summer 8-11-2023

Document Type

Thesis (Ph.D.)

Department or Program

Cancer Biology

First Advisor

Brock C. Christensen


Bladder cancer patients receive frequent screening due to the high tumor recurrence rate (more than 60%). Nowadays, the conventional monitoring method relies on cystoscopy which is highly invasive and increases patient morbidity and burden to the health care system with frequent follow-up. As a result, it is urgent to explore novel markers related to the outcomes of bladder cancer. Immune profiles have been associated with cancer outcomes and may have the potential to be biomarkers for outcomes management. However, little work has been conducted to investigate the associations of immune cell profiles with bladder cancer outcomes. Here, I utilized the Illumina HumanMethylationEPIC array to measure DNA methylation profiles of peripheral blood and matched tumor tissues of bladder cancer cases recruited in a population-based cohort study in New Hampshire. Then, cell-type deconvolution was applied to quantify immune cell-type proportions, and three epigenetic clocks were estimated for calculating age acceleration. Cox proportional hazard models were performed to test the association of methylation-derived profiles with bladder cancer outcomes. The partDSA algorithm and a semi-supervised recursively partitioned mixture model were conducted to determine overall survival groups based on immune cell profiles, clinical variables, and DNA methylation level. We used an epigenome‐wide association study approach adjusting for immune cell profiles to identify CpG sites associated with the hazard of bladder cancer outcomes, and then, those identified CpG sites were used for enrichment analyses. Finally, we evaluated the association between circulating immune cell-type proportions with the cell-type proportions in the tumor microenvironment. We demonstrated that highly circulating CD4T memory and CD8T memory cell proportions were significantly associated with a decreased hazard of tumor recurrence or death, whereas high neutrophil cell proportion, NLR, and age acceleration were associated with an increased hazard of tumor recurrence or death. Collectively, we identified associations of methylation-derived immune profiles and age acceleration with bladder cancer outcomes that may facilitate the development of bladder cancer prognostic biomarkers.

Original Citation

Chen JQ, Salas LA, Wiencke JK, Koestler DC, Molinaro AM, Andrew AS, Seigne JD, Karagas MR, Kelsey KT, Christensen BC. Immune profiles and DNA methylation alterations related with non-muscle-invasive bladder cancer outcomes. Clin Epigenetics. 2022 Jan 21;14(1):14. doi: 10.1186/s13148-022-01234-6. PMID: 35063012; PMCID: PMC8783448.

Chen JQ, Salas LA, Wiencke JK, Koestler DC, Molinaro AM, Andrew AS, Seigne JD, Karagas MR, Kelsey KT, Christensen BC. Genome-scale methylation analysis identifies immune profiles and age acceleration associations with bladder cancer outcomes. Cancer Epidemiol Biomarkers Prev. 2023 Aug 1:EPI-23-0331. doi: 10.1158/1055-9965.EPI-23-0331. Epub ahead of print. PMID: 37527159.