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Background: Parent of origin-specific allelic expression of imprinted genes is epigenetically controlled. In cancer, imprinted genes undergo both genomic and epigenomic alterations, including frequent copy number changes. We investigated whether copy number loss or gain of imprinted genes in cancer cell lines is associated with response to chemotherapy treatment. Results: We analyzed 198 human imprinted genes including protein-coding genes and noncoding RNA genes using data from tumor cell lines from the Cancer Cell Line Encyclopedia and Genomics of Drug Sensitivity in Cancer datasets. We examined whether copy number of the imprinted genes in 35 different genome locations was associated with response to cancer drug treatment. We also analyzed associations of pretreatment expression and DNA methylation of imprinted genes with drug response. Higher copy number of BLCAP, GNAS, NNAT, GNAS-AS1, HM13, MIR296, MIR298, and PSIMCT-1 in the chromosomal region 20q11-q13.32 was associated with resistance to multiple antitumor agents. Increased expression of BLCAP and HM13 was also associated with drug resistance, whereas higher methylation of gene regions of BLCAP, NNAT, SGK2, and GNAS was associated with drug sensitivity. While expression and methylation of imprinted genes in several other chromosomal regions was also associated with drug response and many imprinted genes in different chromosomal locations showed a considerable copy number variation, only imprinted genes at 20q11-q13.32 had a consistent association of their copy number with drug response. Copy number values among the imprinted genes in the 20q11-q13.32 region were strongly correlated. They were also correlated with the copy number of cancer-related non-imprinted genes MYBL2, AURKA, and ZNF217 in that chromosomal region. Expression of genes at 20q11-q13.32 was associated with ex vivo drug response in primary tumor samples from the Beat AML 1.0 acute myeloid leukemia patient cohort. Association of the increased copy number of the 20q11-q13.32 region with drug resistance may be complex and could involve multiple genes. Conclusions: Copy number of imprinted and non-imprinted genes in the chromosomal region 20q11-q13.32 was associated with cancer drug resistance. The genes in this chromosomal region may have a modulating effect on tumor response to chemotherapy. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]