Expression and Prognostic Implications of Lynch Syndrome-Related Genes in Bladder Cancer
Cancer Genetics and Therapeutics
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Primary Categories:
- Genomic Medicine
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Secondary Categories:
- Genomic Medicine
Introduction:
Lynch syndrome (LS) is an autosomal-dominant familial cancer syndrome caused by germline mutations in DNA mismatch repair genes, specifically MSH2, MSH6, MLH1, PMS2, and EPCAM. Studies indicate that patients with LS have a higher risk of developing upper tract urothelial carcinoma (UTUC) and bladder cancer (BLCA). These LS genes hold promise for advancing early detection and targeted therapies to improve BLCA treatment outcomes. The present study aims to conduct a bioinformatics analysis of somatic variants in these five LS genes in BLCA, utilizing extensive online databases.
Methods:
The dataset was obtained from the BLCA subset of The Cancer Genome Atlas (TCGA), PanCancer Atlas, via cBioPortal. It includes 411 BLCA samples and 19 controls. We conducted differential expression analysis, using Pearson’s correlation to examine relationships based on mRNA expressions and protein-protein interactions (PPI) network analysis through STRING to investigate interactions among related proteins. We also correlated genomic profiling with clinical presentations by comparing gene expression between BLCA samples and normal controls, as well as across various cancer stages, using UALCAN. Overall survival (OS) analysis was conducted in relation to gene expression via the KM plotter, with results presented as survival curves, hazard ratios (HRs) with 95% confidence intervals, and log-rank p-values. Additionally, immunohistochemical patterns from the Human Protein Atlas were analyzed to assess histopathological associations.
Results:
PPI network analysis revealed a strong association among MSH6, MLH1, and PMS2. In the mRNA expression correlation analysis, only MSH2 and MSH6 showed a significant positive correlation, with no notable correlations among the others. mRNA expression levels for most genes, excluding MLH1, were significantly higher in BLCA tissues than in normal tissues. Notably, MSH2, MSH6, PMS2, and EPCAM showed marked overexpression in stage II BLCA and beyond. In OS analysis, elevated expression of MSH6 and PMS2 was linked to poorer survival outcomes, with median HRs of 1.39 (95% CI 1.03-1.89) and 1.45 (95% CI 1.03-2.06), respectively. Histopathologically, MSH2 and MSH6 exhibited strong nuclear staining in BLCA samples.
Conclusion:
In BLCA patients, our study showed MSH2, MSH6, PMS2, and EPCAM are significantly overexpressed in tumor tissues compared to normal tissues. Expression of all four genes is notably higher in stage II and beyond. Furthermore, overexpression of MSH6 and PMS2 was associated with poorer OS, highlighting their potential as prognostic markers. These results support the role of LS genes as promising biomarkers for BLCA treatment and as potential therapeutic targets.
Lynch syndrome (LS) is an autosomal-dominant familial cancer syndrome caused by germline mutations in DNA mismatch repair genes, specifically MSH2, MSH6, MLH1, PMS2, and EPCAM. Studies indicate that patients with LS have a higher risk of developing upper tract urothelial carcinoma (UTUC) and bladder cancer (BLCA). These LS genes hold promise for advancing early detection and targeted therapies to improve BLCA treatment outcomes. The present study aims to conduct a bioinformatics analysis of somatic variants in these five LS genes in BLCA, utilizing extensive online databases.
Methods:
The dataset was obtained from the BLCA subset of The Cancer Genome Atlas (TCGA), PanCancer Atlas, via cBioPortal. It includes 411 BLCA samples and 19 controls. We conducted differential expression analysis, using Pearson’s correlation to examine relationships based on mRNA expressions and protein-protein interactions (PPI) network analysis through STRING to investigate interactions among related proteins. We also correlated genomic profiling with clinical presentations by comparing gene expression between BLCA samples and normal controls, as well as across various cancer stages, using UALCAN. Overall survival (OS) analysis was conducted in relation to gene expression via the KM plotter, with results presented as survival curves, hazard ratios (HRs) with 95% confidence intervals, and log-rank p-values. Additionally, immunohistochemical patterns from the Human Protein Atlas were analyzed to assess histopathological associations.
Results:
PPI network analysis revealed a strong association among MSH6, MLH1, and PMS2. In the mRNA expression correlation analysis, only MSH2 and MSH6 showed a significant positive correlation, with no notable correlations among the others. mRNA expression levels for most genes, excluding MLH1, were significantly higher in BLCA tissues than in normal tissues. Notably, MSH2, MSH6, PMS2, and EPCAM showed marked overexpression in stage II BLCA and beyond. In OS analysis, elevated expression of MSH6 and PMS2 was linked to poorer survival outcomes, with median HRs of 1.39 (95% CI 1.03-1.89) and 1.45 (95% CI 1.03-2.06), respectively. Histopathologically, MSH2 and MSH6 exhibited strong nuclear staining in BLCA samples.
Conclusion:
In BLCA patients, our study showed MSH2, MSH6, PMS2, and EPCAM are significantly overexpressed in tumor tissues compared to normal tissues. Expression of all four genes is notably higher in stage II and beyond. Furthermore, overexpression of MSH6 and PMS2 was associated with poorer OS, highlighting their potential as prognostic markers. These results support the role of LS genes as promising biomarkers for BLCA treatment and as potential therapeutic targets.