Integrated bulk-single-cell transcriptomics identifies IL17RB as a candidate prognostic marker in colon cancer

Patients with colon cancer can experience substantially different outcomes despite comparable anatomical stage, highlighting the need for molecular markers that complement conventional clinicopathological risk assessment. The interleukin-17 (IL-17) cytokine family has context-dependent roles in mucosal inflammation and tumour biology, but the prognostic relevance and cellular context of individual IL-17 receptors in colon cancer remain incompletely characterised. A prespecified family-wide analysis of 11 IL-17 ligands and receptors was performed in the GSE39582 Discovery cohort using continuous-expression Cox regression with Benjamini-Hochberg correction. The lead candidate, IL17RB, was evaluated in the predefined GSE39582 Validation subset and independently in TCGA-COAD, followed by clinical and molecular adjustment, model diagnostics, influence analyses and prognostic-model evaluation. Donor-aware single-cell analysis of GSE178341, exploratory Human Protein Atlas immunohistochemistry and DepMap Public 26Q1 colon adenocarcinoma cell-line analysis were used to characterise the cellular, protein-level and experimental-model context of IL17RB. IL17RB showed the strongest overall-survival association in the GSE39582 Discovery cohort (HR per 1-SD increase = 0.780, 95% CI 0.672-0.904; P < 0.001; q = 0.011). The association was directionally concordant in the predefined Validation subset (HR = 0.722, 95% CI 0.533-0.979; P = 0.036), although it did not remain significant after family-wide correction (q = 0.122), and was also observed for relapse-free survival. In TCGA-COAD, the simple linear association was weaker, whereas clinically adjusted spline modelling showed significant overall association and non-linearity (P = 0.003 and P = 0.005, respectively). Clinical and molecular sensitivity analyses generally retained the direction of association. Addition of IL17RB produced modest improvements in prognostic-model performance, but confidence intervals around incremental Validation metrics included zero. Donor-aware single-cell analysis localised IL17RB predominantly to epithelial cells and showed higher expression within an independently annotated tuft-cell cluster. Exploratory HPA assessment showed predominantly low or undetectable IL-17RB protein staining in colon adenocarcinoma, whereas the primary continuous DepMap analysis showed no significant association between IL17RB and the predefined tuft-cell transcriptional programme. IL17RB represents a candidate prognostic marker with complementary epithelial and tuft-cell-associated biological context. Its incremental contribution to clinical risk prediction remains modest and requires additional independent validation. Higher IL17RB expression was associated with favourable survival most consistently in GSE39582, while TCGA-COAD revealed a more complex nonlinear relationship. The combined findings support further prognostic and functional investigation of IL17RB but do not establish clinical utility, mechanistic function or therapeutic targetability.

The online version contains supplementary material available at https://doi.org/10.1007/s40203-026-00746-w.