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Summary: Symptoms of depression are common among patients before surgery. Depression may be associated with worse postoperative pain and other pain‐related outcomes. This review aimed to characterise the impact of pre‐operative depression on postoperative pain outcomes. We conducted a systematic review of observational studies that reported an association between pre‐operative depression and pain outcomes after major surgery. Multilevel random effects meta‐analyses were conducted to pool standardised mean differences and 95%CI for postoperative pain scores in patients with depression compared with those without depression, at different time intervals. A meta‐analysis was performed for studies reporting change in pain scores from the pre‐operative period to any time‐point after surgery. Sixty studies (n = 501,962) were included in the overall review, of which 18 were eligible for meta‐analysis. Pre‐operative depression was associated with greater pain scores at < 72 h (standardised mean difference 0.97 (95%CI 0.37–1.56), p = 0.009, I2 = 41%; moderate certainty) and > 6 months (standardised mean difference 0.45 (95%CI 0.23–0.68), p < 0.001, I2 = 78%; low certainty) after surgery, but not at 3–6 months after surgery (standardised mean difference 0.54 (95%CI ‐0.06–1.15), p = 0.07, I2 = 83%; very low certainty). The change in pain scores from pre‐operative baseline to 1–2 years after surgery was similar between patients with and without pre‐operative depression (standardised mean difference 0.13 (95%CI ‐0.06–0.32), p = 0.15, I2 = 54%; very low certainty). Overall, pre‐existing depression before surgery was associated with worse pain severity postoperatively. Our findings highlight the importance of incorporating psychological care into current postoperative pain management approaches in patients with depression. [ABSTRACT FROM AUTHOR]

Background: Delirium is a common and potentially serious complication after major surgery. A previous history of depression is a known risk factor for experiencing delirium in patients admitted to the hospital, but the generalised risk has not been estimated in surgical patients., Methods: We conducted a systematic review and meta-analysis of studies reporting the incidence or relative risk (or relative odds) of delirium in the immediate postoperative period for adults with pre-operative depression. We included studies that defined depression as either a formal pre-existing diagnosis or having clinically important depressive symptoms measured using a patient-reported instrument before surgery. Multilevel random effects meta-analyses were used to estimate the pooled incidences and pooled relative risks. We also conducted subgroup analyses by various study-level characteristics to identify important moderators of pooled estimates., Results: Forty-two studies (n = 4,664,051) from five continents were included. The pooled incidence of postoperative delirium for patients with pre-operative depression was 29% (95%CI 17-43%, I 2  = 99.0%), compared with 15% (95%CI 6-28%, I 2  = 99.8%) in patients without pre-operative depression and 21% (95% CI 11-33%, I 2  = 99.8%) in the cohorts overall. For patients with pre-operative depression, the risk of delirium was 1.91 times greater (95%CI 1.68-2.17, I 2  = 42.0%) compared with patients without pre-operative depression., Conclusions: Patients with a previous diagnosis of depression or clinically important depressive symptoms before surgery have substantially greater risk of experiencing delirium after surgery. Clinicians and patients should be informed of these increased risks. Robust screening and other risk mitigation strategies for postoperative delirium are warranted, especially for patients with pre-operative depression., (© 2024 The Author(s). Anaesthesia published by John Wiley & Sons Ltd on behalf of Association of Anaesthetists.)

Dysregulation of histone lysine methyltransferases and demethylases is one of the major mechanisms driving the epigenetic reprogramming of transcriptional networks in castration-resistant prostate cancer (CRPC). In addition to their canonical histone targets, some of these factors can modify critical transcription factors, further impacting oncogenic transcription programs. Our recent report demonstrated that LSD1 can demethylate the lysine 270 of FOXA1 in prostate cancer (PCa) cells, leading to the stabilization of FOXA1 chromatin binding. This process enhances the activities of the androgen receptor and other transcription factors that rely on FOXA1 as a pioneer factor. However, the identity of the methyltransferase responsible for FOXA1 methylation and negative regulation of the FOXA1-LSD1 oncogenic axis remains unknown. SETD7 was initially identified as a transcriptional activator through its methylation of histone 3 lysine 4, but its function as a methyltransferase on nonhistone substrates remains poorly understood, particularly in the context of PCa progression. In this study, we reveal that SETD7 primarily acts as a transcriptional repressor in CRPC cells by functioning as the major methyltransferase targeting FOXA1-K270. This methylation disrupts FOXA1-mediated transcription. Consistent with its molecular function, we found that SETD7 confers tumor suppressor activity in PCa cells. Moreover, loss of SETD7 expression is significantly associated with PCa progression and tumor aggressiveness. Overall, our study provides mechanistic insights into the tumor-suppressive and transcriptional repression activities of SETD7 in mediating PCa progression and therapy resistance.

Analysis of DNA methylation is a valuable tool to understand disease progression and is increasingly being used to create diagnostic and prognostic clinical biomarkers. While conversion of cytosine to 5-methylcytosine (5mC) commonly results in transcriptional repression, further conversion to 5-hydroxymethylcytosine (5hmC) is associated with transcriptional activation. Here we perform the first study integrating whole-genome 5hmC with DNA, 5mC, and transcriptome sequencing in clinical samples of benign, localized, and advanced prostate cancer. 5hmC is shown to mark activation of cancer drivers and downstream targets. Furthermore, 5hmC sequencing revealed profoundly altered cell states throughout the disease course, characterized by increased proliferation, oncogenic signaling, dedifferentiation, and lineage plasticity to neuroendocrine and gastrointestinal lineages. Finally, 5hmC sequencing of cell-free DNA from patients with metastatic disease proved useful as a prognostic biomarker able to identify an aggressive subtype of prostate cancer using the genes TOP2A and EZH2, previously only detectable by transcriptomic analysis of solid tumor biopsies. Overall, these findings reveal that 5hmC marks epigenomic activation in prostate cancer and identify hallmarks of prostate cancer progression with potential as biomarkers of aggressive disease., Significance: In prostate cancer, 5-hydroxymethylcytosine delineates oncogene activation and stage-specific cell states and can be analyzed in liquid biopsies to detect cancer phenotypes. See related article by Wu and Attard, p. 3880., (©2022 The Authors; Published by the American Association for Cancer Research.)

Metastatic prostate cancer remains a major clinical challenge and metastatic lesions are highly heterogeneous and difficult to biopsy. Liquid biopsy provides opportunities to gain insights into the underlying biology. Here, using the highly sensitive enrichment-based sequencing technology, we provide analysis of 60 and 175 plasma DNA methylomes from patients with localized and metastatic prostate cancer, respectively. We show that the cell-free DNA methylome can capture variations beyond the tumor. A global hypermethylation in metastatic samples is observed, coupled with hypomethylation in the pericentromeric regions. Hypermethylation at the promoter of a glucocorticoid receptor gene NR3C1 is associated with a decreased immune signature. The cell-free DNA methylome is reflective of clinical outcomes and can distinguish different disease types with 0.989 prediction accuracy. Finally, we show the ability of predicting copy number alterations from the data, providing opportunities for joint genetic and epigenetic analysis on limited biological samples., (© 2022. The Author(s).)

Prostate cancer (PCa) risk-associated SNPs are enriched in noncoding cis-regulatory elements (rCREs), yet their modi operandi and clinical impact remain elusive. Here, we perform CRISPRi screens of 260 rCREs in PCa cell lines. We find that rCREs harboring high risk SNPs are more essential for cell proliferation and H3K27ac occupancy is a strong indicator of essentiality. We also show that cell-line-specific essential rCREs are enriched in the 8q24.21 region, with the rs11986220-containing rCRE regulating MYC and PVT1 expression, cell proliferation and tumorigenesis in a cell-line-specific manner, depending on DNA methylation-orchestrated occupancy of a CTCF binding site in between this rCRE and the MYC promoter. We demonstrate that CTCF deposition at this site as measured by DNA methylation level is highly variable in prostate specimens, and observe the MYC eQTL in the 8q24.21 locus in individuals with low CTCF binding. Together our findings highlight a causal mechanism synergistically driven by a risk SNP and DNA methylation-mediated 3D genome architecture, advocating for the integration of genetics and epigenetics in assessing risks conferred by genetic predispositions.

FOXA1 functions as a pioneer transcription factor by facilitating the access to chromatin for steroid hormone receptors, such as androgen receptor and estrogen receptor 1-4 , but mechanisms regulating its binding to chromatin remain elusive. LSD1 (KDM1A) acts as a transcriptional repressor by demethylating mono/dimethylated histone H3 lysine 4 (H3K4me1/2) 5,6 , but also acts as a steroid hormone receptor coactivator through mechanisms that are unclear. Here we show, in prostate cancer cells, that LSD1 associates with FOXA1 and active enhancer markers, and that LSD1 inhibition globally disrupts FOXA1 chromatin binding. Mechanistically, we demonstrate that LSD1 positively regulates FOXA1 binding by demethylating lysine 270, adjacent to the wing2 region of the FOXA1 DNA-binding domain. Acting through FOXA1, LSD1 inhibition broadly disrupted androgen-receptor binding and its transcriptional output, and dramatically decreased prostate cancer growth alone and in synergy with androgen-receptor antagonist treatment in vivo. These mechanistic insights suggest new therapeutic strategies in steroid-driven cancers.

The cancer transcriptome is remarkably complex, including low-abundance transcripts, many not polyadenylated. To fully characterize the transcriptome of localized prostate cancer, we performed ultra-deep total RNA-seq on 144 tumors with rich clinical annotation. This revealed a linear transcriptomic subtype associated with the aggressive intraductal carcinoma sub-histology and a fusion profile that differentiates localized from metastatic disease. Analysis of back-splicing events showed widespread RNA circularization, with the average tumor expressing 7,232 circular RNAs (circRNAs). The degree of circRNA production was correlated to disease progression in multiple patient cohorts. Loss-of-function screening identified 11.3% of highly abundant circRNAs as essential for cell proliferation; for ∼90% of these, their parental linear transcripts were not essential. Individual circRNAs can have distinct functions, with circCSNK1G3 promoting cell growth by interacting with miR-181. These data advocate for adoption of ultra-deep RNA-seq without poly-A selection to interrogate both linear and circular transcriptomes., (Copyright © 2019 Elsevier Inc. All rights reserved.)