Identification of cell differentiation trajectory-related gene signature to reveal the prognostic significance and immune landscape in prostate cancer based on multiomics analysis.

BACKGROUND

In the context of prostate cancer (PCa), the occurrence of biochemical recurrence (BCR) stands out as a pivotal factor significantly impacting prognosis, potentially leading to metastasis and mortality. However, the early detection of BCR poses a substantial challenge for PCa patients. There is an urgent need to pinpoint hub genes that can serve as predictive indicators for BCR in PCa patients.

METHODS

Our primary goal was to identify cell differentiation trajectory-related gene signature in PCa patients by pseudo-time trajectory analysis. We further explored the functional enrichment of overlapped marker genes and probed clinically relevant modules and BCR-related genes using Weighted Gene Co-expression Network Analysis (WGCNA) in PCa patients. Key genes predicting recurrence-free survival were meticulously identified through univariate and multivariate Cox regression analyses. Subsequently, these genes were utilized to construct a prognostic gene signature, the expression, predictive efficacy, putative functions, and immunological landscape of which were thoroughly validated. Additionally, we employed immunohistochemistry (IHC) and a western blotting assay to quantify the expression of PYCR1 in clinical samples.

RESULTS

Our single-cell RNA (scRNA) sequencing analysis unveiled three subgroups characterized by distinct differentiation trajectories, and the marker genes associated with these groups were extracted from PCa patients. These marker genes successfully classified the PCa sample into two molecular subtypes, demonstrating a robust correlation with clinical characteristics and recurrence-free survival. Through WGCNA and Lasso analysis, we identified four hub genes (KLK3, CD38, FASN, and PYCR1) to construct a risk profile of prognostic genes linked to BCR. Notably, the high-risk patient group exhibited elevated levels of B cell naive, Macrophage M0, and Macrophage M2 infiltration, while the low-risk group displayed higher levels of T cells CD4 memory activated and monocyte infiltration. Furthermore, IHC and western blotting assays confirmed the heightened expression of PYCR1 in PCa tissues.

CONCLUSION

This study leveraged the differentiation trajectory and genetic variability of the microenvironment to uncover crucial prognostic genes associated with BCR in PCa patients. These findings present novel perspectives for tailoring treatment strategies for PCa patients on an individualized basis.