Enhancer RNA (eRNA) is a type of noncoding RNA transcribed from the enhancer. Although critical roles of eRNA in gene transcription control have been increasingly realized, the systemic landscape and potential function of eRNAs in cancer remains largely unexplored. Here, we report the integration of multi-omics and pharmacogenomics data across large-scale patient samples and cancer cell lines. We observe a cancer-/lineage-specificity of eRNAs, which may be largely driven by tissue-specific TFs. eRNAs are involved in multiple cancer signaling pathways through putatively regulating their target genes, including clinically actionable genes and immune checkpoints. They may also affect drug response by within-pathway or cross-pathway means. We characterize the oncogenic potential and therapeutic liability of one eRNA, NET1e, supporting the clinical feasibility of eRNA-targeted therapy. We identify a panel of clinically relevant eRNAs and developed a user-friendly data portal. Our study reveals the transcriptional landscape and clinical utility of eRNAs in cancer.

Accumulated evidence supports the existence of sex-associated differences in immune systems. Understanding the role of sex in immune-related adverse events (irAEs) is important for management of irAE in patients receiving immunotherapy. We performed meta-analysis on published clinical study data and multivariable logistic regression on pharmacovigilance data and applied a propensity algorithm to The Cancer Genome Atlas omics data. We further validated our observations in 2 independent in-house cohorts of 179 and 767 cancer patients treated with immune checkpoint inhibitors. A meta-analysis using 13 clinical studies that reported on 1096 female patients (36.8%, 95% confidence interval [CI] = 35.0% to 38.5%) and 1886 male patients (63.2%, 95% CI = 61.5% to 65.0%) demonstrated no statistically significant irAE risk difference between the sexes (odds ratio [OR] = 1.19, 95% CI = 0.91 to 1.54, 2-sided P = .21). Multivariable logistic regression analysis of 12 225 patients from the Food and drug administration Adverse Event Reporting System (FAERS) and 10 979 patients from VigiBase showed no statistically significant difference in irAEs by sex. A propensity score algorithm used on multi-omics data for 6019 patients from The Cancer Genome Atlas found no statistically significant difference by sex for irAE-related factors or pathways. The retrospective analysis of 2 in-house patient cohorts validated these results (OR = 1.55, 95% CI = 0.98 to 2.47, false discovery rate = 0.13, for cohort 1; OR = 1.16, 95% CI = 0.86 to 1.57, false discovery rate = 0.39, for cohort 2). We observed minimal sex-associated differences in irAEs among cancer patients who received immune checkpoint inhibitor therapy. It may be unnecessary to consider sex effects for irAE management in clinical practice.

RNA solution for a genetic problem: Phenylketonuria provides a classic case of the benefit of newborn metabolic screening: It is a single-gene disease that can be detected at birth, and its neurological effects can be prevented by dietary therapy. Unfortunately, this is not always straightforward because the disease-causing mutations in phenylalanine hydroxylase vary between patients and affect the severity of the phenotype, such that some patients’ symptoms do not fully respond to the available interventions. Li et al . identified two long noncoding RNAs, one in mice and one in humans, that interact with phenylalanine hydroxylase and modulate its function (see the Perspective by Ben-Tov Perry and Ulitsky). Administration of modified RNAs mimicking their effects ameliorated the disease phenotype in mouse models of phenylketonuria. —YN