Single-Cell Analysis Combined with Mendelian Randomization Identifies Genes Associated with Prostate Cancer Cells.

Purpose: Prostate cancer is the second most common male cancer, with incidence increasing with age. When prostate cancer extends beyond the prostatic capsule, treatment options and prognosis change significantly. This study aims to investigate prognostic genes related to capsular invasion in prostate cancer by integrating single-cell data with Mendelian randomization (MR) analysis.

Materials and methods: Single-cell sequencing data from six prostate cancer cases were obtained from the Gene Expression Omnibus (GEO) database. Cell clustering and annotation were performed using R, and high-dimensional weighted gene co-expression network analysis (hdWGCNA) identified differentially expressed genes in advanced-stage cancer. Single nucleotide polymorphism loci corresponding to these genes were retrieved from the UK Biobank (UKB), and MR exposure data were acquired from the ukb-b-13348 dataset. MR analysis assessed the impact of hdWGCNA-identified genes. Clinical and gene expression data from TCGA and GEO were analyzed using univariate Cox regression to evaluate gene effects on prognosis. Cellular functional experiments and immunohistochemistry assessed gene expression and function in prostate cancer.

Results: We employed the Seurat package for quality control and integration of single-cell data from four patients. hdWGCNA identified three modules, from which 200 genes were selected. The combined analysis of eQTL and MR revealed that TMEM59, JUNB, NECTIN2, OSBPL10, ATF3, and WLS may have relevant associations with prostate cancer. Further investigation using TCGA and GEO data suggested that TMEM59 might act as a protective factor in prostate cancer. Cellular experiments confirmed that TMEM59 knockdown enhanced the proliferation and invasion capabilities of prostate cancer cells. Immunohistochemistry demonstrated a significant decrease in TMEM59 expression in both normal and tumor tissues, particularly in the tumor group.

Conclusions: These findings suggest that TMEM59 may play a crucial role in the progression of prostate cancer and could serve as a prognostic predictor and therapeutic target for the disease.