Depression-related gene signature characterizes prognostic subtypes and therapeutic sensitivities in colorectal...

Depression substantially influences the occurrence, progression, and prognosis of colorectal cancer (CRC). Nevertheless, validated biomarker signatures that capture depression-associated prognostic signals in CRC remain to be established. This study aimed to develop a depression‑related gene (DRG) prognostic classifier and preliminarily evaluate its predictive biomarker utility in CRC. In the GSE39582 training cohort, we performed univariate Cox regression to identify overall survival (OS)‑associated DRGs sourced from previous studies. A candidate multi‑gene prognostic classifier was subsequently developed using least absolute shrinkage and selection operator (LASSO) regression followed by multivariate Cox analysis. The discriminatory performance of the signature was evaluated via Kaplan-Meier survival analysis and receiver operating characteristic (ROC) curves. To explore underlying biological patterns, we conducted comprehensive evaluations of the immune microenvironment, chemotherapeutic drug responsiveness, and functional enrichment among differentially expressed genes (DEGs) across risk‑defined subgroups. Furthermore, the potential biomarker relevance of signature genes in CRC was investigated through in vitro proliferation and migration assays. Among 702 DRGs, 71 exhibited significant associations with OS. The resulting 14‑gene signature demonstrated area under the curve (AUC) values of 0.64, 0.71, and 0.72 for 1‑, 3‑, and 5‑year OS in the GSE39582 training set. Patients classified into the high‑risk stratum showed markedly worse survival and expression profiles suggestive of reduced chemosensitivity to both 5‑fluorouracil and oxaliplatin. Among the 14 genes, METTL9 was identified as overexpressed in CRC tissues, showed association with unfavorable clinical outcomes, and exhibited enhanced proliferative and migratory capacities in CRC cells. We developed a risk stratification framework comprising 14 DRGs that showed moderate prognostic performance in CRC. This signature may serve as a candidate prognostic biomarker and highlights the potential relevance of depression-related molecular pathways in CRC, pending validation in prospective cohorts.

The online version contains supplementary material available at https://doi.org/10.1007/s10616-026-01075-8.