Abstract
Folate metabolism is critical for the maintenance of genomic stability due to its regulatory ability to methylation, nucleotide metabolism, and reduction capabilities in cancer cells. However, the prognostic value of folate metabolism-related genes has not been clarified, especially in bladder cancer (BLCA). 91 folate metabolism-related genes were retrieved from the public database. TCGA-BLCA cohort, obtained from the Cancer Genome Atlas, was selected for training, while GSE13507, GSE31684, and GSE32894, downloaded from the Gene Expression Omnibus, and 35 BLCA samples collected from the local hospital were used for external validation. Through genomic difference detection, protein-protein interaction network analysis, LASSO regression, and Cox regression, a three-gene signature, including ATIC, INS, and MTHFD1L, was constructed. The signature was a reliable prognosis predictor across multiple independent cohorts (pooled hazard ratio = 2.79, 95% confidence interval = 1.79–4.33). The signature was associated with the BLCA malignant degree, which was validated in the local clinical samples (P < 0.01) and multiple cell lines (all P < 0.05). Additionally, the TIDE algorithm, GSE111636 cohort, and IMvigor210 cohort indicated that the signature was a promising tool to evaluate the immunotherapeutic response. Collectively, a folate metabolism-related gene signature was constructed to predict the prognosis and immunotherapeutic sensitivity in BLCA, which was verified in multiple large-scale cohorts, clinical samples, and cellular experiments, providing novel insights into the biological mechanisms.
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All the data from the public databases could be obtained on the website links provided in this paper. The R codes and the RT-qPCR experimental data could be obtained from the corresponding author upon reasonable request.
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CXL designed the whole study, modified the format, and polished the English language. XCL provided the financial support, analyzed the original data, and collected the clinical samples. CXC wrote the original manuscript and conducted the experiments. PX helped to make and beautify the figures. BSC and ABX contributed to manuscript revision. All authors reviewed the manuscript.
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Xincheng Liu and Chunxiao Chen contributed equally.
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Liu, X., Chen, C., Xu, P. et al. Development and experimental validation of a folate metabolism-related gene signature to predict the prognosis and immunotherapeutic sensitivity in bladder cancer. Funct Integr Genomics 23, 291 (2023). https://doi.org/10.1007/s10142-023-01205-x
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DOI: https://doi.org/10.1007/s10142-023-01205-x