2026 ECNP Congress

PS03-3224

How does inflammation shape cancer-related transcriptional signatures in individuals with depression?

Kierra Morris — M. Marizzoni, C. Bottanelli, S. Saleri, A. Cattaneo, M. Kose, G. Lombardo, N. Mariani, C. Worrell, Z. Zajkowska, E. Bullmore, V. Mondelli, C. Pariante, L. Sforzini · Institute of Psychiatry- Psychology and Neuroscience IoPPN- King's College London, Psychological Medicine, London, United Kingdom

2026 ECNP Congress

Introduction

Growing research is demonstrating that individuals with Major Depressive Disorder (MDD) are at higher risk of developing cancer [1]. Inflammation is widely associated with multiple stages of cancer development [2] and higher levels of inflammation have been identified in individuals with depression [3]. However, we still do not fully understand the biological mechanisms that underlie this comorbidity.

Aims

In this study, we explore cancer-related genes across RNA-sequencing transcripts derived from a multi-site observational study (BIODEP) of immune-related biomarkers in individuals with MDD to identify shared transcriptional signatures.

Methods

Through a comprehensive review of relevant gene expression patterns in the Pan Cancer Atlas as well as the Network of Cancer Genes Database, we created a list of 659 cancer-related genes. We then investigated how these genes overlap with generated DE transcripts of the BIODEP study [4]. We included n=105 participants with MDD and n=34 non-depressed healthy controls (HC). The MDD group was further stratified by levels of C-Reactive Protein (CRP) in CRP<1 mg/L (n= 39), 1-3 mg/L (n = 31), and >3 mg/L (n=35). Gene expression was measured using mRNA levels from RNASeq data and differential expression was analysed with the DESeq2 software. A total of 4,131 transcripts were found to be differentially regulated across group comparisons involving each of the MDD groups and HC. Gene Set Variation Analysis (GSVA) was performed to evaluate gene enrichment scores across groups.

Results

We found 59 cancer-related transcripts differentially expressed among the groups (p <.05 and fold change (FC) ±|1.2|), with unique profiles associated with MDD and the inflammation status. Transcriptional signatures of MDD participants with higher levels of inflammation (CRP>3) were distinct from those with lower inflammation (CRP<1) and controls, with 17 shared transcripts consistently up- (BCL2L1, WWTR1, NRG1, CD274, RPL22, BCL6, HOXA9, TNFRSF17, ERG, ERBB4, PDCD1LG2, TENT5C) or down-regulated (GATA2, NTRK1, FBLN2, KIT, PRF1). Additionally, we found 2 transcripts up-regulated (ROBO2 and OLIG2) and 5 down-regulated (TSHR, ZNF429, BCL2L1, ARHGEF12, IGF2BP2) in both (CRP 1-3) and (CRP<1) vs controls, highlighting shared transcripts between individuals with MDD and low-to-intermediate levels of inflammation compared with controls. Sub-analyses on (CRP <1) and controls with similar levels of inflammation (n=20) also confirm this pattern of transcriptional down-regulation (ZNF49, TSHR, BCL2L1, ARHGEF12), suggesting that these differences are not solely explained by inflammation. In addition, GSVA analyses revealed a significant difference in enrichment scores (Wilcoxon W = 253, p = 0.02796,) between participants with MDD and CRP<1 and controls selected for similar levels of inflammation.

Conclusions

These preliminary findings highlight differential expression of cancer-related transcripts in MDD. While inflammation may shape these distinct molecular profiles and is a key factor in the comorbidity between cancer and depression, other biological pathways might contribute to this association, as highlighted by transcriptional differences with similar levels of low inflammation.

References

  1. Mössinger, H., & Kostev, K. (2023). Depression Is Associated with an Increased Risk of Subsequent Cancer Diagnosis: A Retrospective Cohort Study with 235,404 Patients. Brain sciences, 13(2), 302. https://doi.org/10.3390/brainsci13020302
  2. Multhoff, G., Molls, M., & Radons, J. (2012). Chronic Inflammation in Cancer Development. Frontiers in Immunology, 2, 98. https://doi.org/10.3389/fimmu.2011.00098
  3. Pitharouli, M. C., Hagenaars, S. P., & Glanville, K. P. (2021). Elevated C-Reactive Protein in Patients With Depression, Independent of Genetic, Health, and Psychosocial Factors: Results From the UK Biobank.
  4. Sforzini, L., Marizzoni, M., Bottanelli, C. et al. Transcriptomic profiles in major depressive disorder: the role of immunometabolic and cell-cycle-related pathways in depression with different levels of inflammation. Mol Psychiatry 30, 1308–1318 (2025). https://doi.org/10.1038/s41380-024-02736-w