Immune profiles and DNA methylation alterations related with non-muscle-invasive bladder cancer outcomes

Abstract

Background Non-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 results We 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. Conclusions 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.

Increased copy number of imprinted genes in the chromosomal region 20q11-q13.32 is associated with resistance to antitumor agents in cancer cell lines

“…2), and therefore either its expression, DNA methylation, or copy number, or a combination of these factors may contribute to drug response. The direction of correlations in our analysis of cell line data was consistent with earlier reports of associations of increased BLCAP protein expression and lower BLCAP promoter methylation with inferior survival of bladder cancer patients [142,143]. Earlier studies showed that BLCAP expression involves different transcripts which are expressed in a promoter-specific and tissue-specific manner and that the BLCAP transcript expressed in human fetal brain is imprinted, with predominantly maternal expression [140].…”

“…The lack of association of genes in that region with survival of AML patients may be explained by multiple factors, e.g., weak to modest associations of individual genes which were associated with drug response, complex drug treatment regimens of the patients involved in the study, and genetic and clinical heterogeneity of the study patients [46]. Some effects of the genes at 20q11-q13.32 analyzed in this study may be tumor-specific, as suggested by the findings of Moreira et al [142] and Chen et al [143] of associations of BLCAP protein expression and promoter methylation levels with survival of bladder cancer patients, which were consistent with our analysis of drug response in pancancer cell lines. Similarly, Anwar et al [37] reported an association of survival of hepatocellular carcinoma patients with increased methylation of several of the same imprinted genes and imprinted gene regions (GNAS at 20q13.32, the DLK1-DIO3 cluster at 14q32.2-q32.31, and ZIM3 at 19q13.43) in primary tumor samples, which were also associated with increased drug sensitivity in our pancancer analysis of tumor cell lines (Additional file 9: Table S6).…”

Deciphering the role of immune cell composition in epigenetic age acceleration: Insights from cell‐type deconvolution applied to human blood epigenetic clocks

“…Specifically in human blood, our previous research employed differentially methylated regions identified between purified leukocyte subtypes to develop a reference‐based deconvolution algorithm, allowing estimation of the distribution of various leukocyte subtypes (Salas et al., 2022). This blood deconvolution approach has been utilized to investigate altered immune cell composition in multiple diseases, such as cancer (Chen et al., 2022, 2023), hypertension (Kresovich et al., 2023), and trisomy 21 (Zhang, Stolrow, et al., 2023).…”

Pre-surgery immune profiles of adult glioma patients

“…Considering this, we sought to ask whether blood immune profiles are altered at baseline and to what extent alterations may be attributed to dexamethasone exposure or tumor subtype prior to surgical resection. Here we estimated leukocyte subtypes using a validated methylation deconvolution method that has an improved accuracy over previous deconvolution methods [ 4 , 13 , 15 , 18 ], has been applied in other studies [ 4 , 19 ] and whose approach has compared favorably to other methods [ 20 ].. We show for the first time that pre-surgery immune subset profiles vary by glioma subtype; most notably, compared with other glioma subtypes, patients with IDHwt GBM had lower levels of all immune subsets except neutrophils, which were higher. We show that immune subsets were higher, except neutrophils which were lower, in controls than in glioma patients.…”