Publications

A sea change has occurred in the treatment options available for metastatic urothelial bladder cancer with the recent Food and Drug Administration approval of 5 immune checkpoint blockade agents for patients who have progressed on platinum-based chemotherapy or are not candidates for cisplatin. Additionally, comprehensive characterization of the landscape of genomic alterations in this disease through The Cancer Genome Atlas and other efforts has detected numerous potential targets for small molecule inhibitors. Detailed analysis of the urothelial carcinoma transcriptome has allowed for molecular subtyping of the disease and the ramifications of these subtypes upon treatment response is an active area of investigation. Coupled with these advances is a critical unmet need to define predictive biomarkers of response to therapy. Here, we highlight select research relevant to the validation and continued discovery of novel biomarkers to advance precision oncology in bladder cancer.

OBJECTIVE

Epigenetic modifications have previously been associated with rheumatoid arthritis (RA). In this study, we aimed to determine whether differential DNA methylation in peripheral blood cell subpopulations is associated with any of 4 clinical outcomes among RA patients.

METHODS

Peripheral blood samples were obtained from 63 patients in the University of California, San Francisco RA cohort (all satisfied the American College of Rheumatology classification criteria; 57 were seropositive for rheumatoid factor and/or anti-cyclic citrullinated protein). Fluorescence-activated cell sorting was used to separate the cells into 4 immune cell subpopulations (CD14+ monocytes, CD19+ B cells, CD4+ naive T cells, and CD4+ memory T cells) per individual, and 229 epigenome-wide DNA methylation profiles were generated using Illumina HumanMethylation450 BeadChips. Differentially methylated positions and regions associated with the Clinical Disease Activity Index score, erosive disease, RA Articular Damage score, Sharp score, medication at time of blood draw, smoking status, and disease duration were identified using robust regression models and empirical Bayes variance estimators.

RESULTS

Differential methylation of CpG sites associated with clinical outcomes was observed in all 4 cell types. Hypomethylated regions in the CYP2E1 and DUSP22 gene promoters were associated with active and erosive disease, respectively. Pathway analyses suggested that the biologic mechanisms underlying each clinical outcome are cell type-specific. Evidence of independent effects on DNA methylation from smoking, medication use, and disease duration were also identified.

CONCLUSION

Methylation signatures specific to RA clinical outcomes may have utility as biomarkers or predictors of exposure, disease progression, and disease severity.