Abstract
BackgroundNon-muscle-invasive bladder cancer (NMIBC) patients receive frequent monitoring because ≥ 70% will have recurrent disease. However, screening is invasive, expensive, and associated with significant morbidity making bladder cancer the most expensive cancer to treat per capita. There is an urgent need to expand the understanding of markers related to recurrence and survival outcomes of NMIBC.Methods and resultsWe used the Illumina HumanMethylationEPIC array to measure peripheral blood DNA methylation profiles of NMIBC patients (N = 603) enrolled in a population-based cohort study in New Hampshire and applied cell type deconvolution to estimate immune cell-type proportions. Using Cox proportional hazard models, we identified that increasing CD4T and CD8T cell proportions were associated with a statistically significant decreased hazard of tumor recurrence or death (CD4T: HR = 0.98, 95% CI = 0.97–1.00; CD8T: HR = 0.97, 95% CI = 0.95–1.00), whereas increasing monocyte proportion and methylation-derived neutrophil-to-lymphocyte ratio (mdNLR) were associated with the increased hazard of tumor recurrence or death (monocyte: HR = 1.04, 95% CI = 1.00–1.07; mdNLR: HR = 1.12, 95% CI = 1.04–1.20). Then, using an epigenome-wide association study (EWAS) approach adjusting for age, sex, smoking status, BCG treatment status, and immune cell profiles, we identified 2528 CpGs associated with the hazard of tumor recurrence or death (P < 0.005). Among these CpGs, the 1572 were associated with an increased hazard and were significantly enriched in open sea regions; the 956 remaining CpGs were associated with a decreased hazard and were significantly enriched in enhancer regions and DNase hypersensitive sites.ConclusionsOur results expand on the knowledge of immune profiles and methylation alteration associated with NMIBC outcomes and represent a first step toward the development of DNA methylation-based biomarkers of tumor recurrence.
Highlights
Non-muscle-invasive bladder cancer (NMIBC) patients receive frequent monitoring because ≥ 70% will have recurrent disease
Our results expand on the knowledge of immune profiles and methylation alteration associated with NMIBC outcomes and represent a first step toward the development of DNA methylation-based biomarkers of tumor recurrence
These findings are consistent with previous studies demonstrating that neutrophil-to-lymphocyte ratio (NLR) was significantly higher in highrisk NMIBC patients [27], and increased NLR was positively associated with poor prognosis [28, 29]
Summary
Non-muscle-invasive bladder cancer (NMIBC) patients receive frequent monitoring because ≥ 70% will have recurrent disease. Seventy-five percent of bladder cancers are diagnosed as low-grade non-muscle invasive tumors, NMIBC [2]. Transurethral excisions can successfully control the disease and mortality from bladder cancer among patients with localized tumors is low, 45% of NMIBC cases have recurrences within 12 months of surgery [6]. Frequent invasive follow-up via cystoscopy without prognostic markers leads to significant patient morbidity and comes with a considerable cost burden to the health care system, estimated at approximately $4 billion dollars annually in the USA [7]. To control the patient and healthcare burdens associated with NMIBC, there is an imminent need for biomarkers to identify those at the highest risk of tumor recurrence
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