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Background: Perioperative cisplatin-based chemotherapy (CBC) can improve the outcome of patients with muscle-invasive bladder cancer (MIBC), but it is still to be defined which patients benefit. Mutations in DNA damage response genes (DDRG) can predict the response to CBC. The value of DDRG expression as a marker of CBC treatment effect remains unclear. Material and methods: RNA expression of the nine key DDRG ( BCL2 ,  BRCA1 ,  BRCA2 ,  ERCC2 ,  ERCC6 ,  FOXM1 ,  RAD50 ,  RAD51 , and  RAD52 ) was assessed by qRT-PCR in a cohort of 61 MICB patients (median age 66 y, 48 males, 13 females) who underwent radical cystectomy in a tertiary care center. The results were validated in the The Cancer Genome Atlas (TCGA) cohort of MIBC ( n  = 383). Gene expression was correlated with disease-free survival (DFS) and overall survival (OS). Subgroup analyses were performed in patients who received adjuvant cisplatin-based chemotherapy (ACBC) (Mannheim  n  = 20 and TCGA  n  = 75). Results: Low expression of  RAD52  was associated with low DFS in both the Mannheim and the TCGA cohorts (Mannheim:  p  = 0.039; TCGA:  p  = 0.017). This was especially apparent in subgroups treated with ACBC (Mannheim:  p  = 0.0059; TCGA:  p  = 0.012). Several other genes showed an influence on DFS in the Mannheim cohort ( BRCA2 ,  ERCC2 ,  FOXM1 ) where low expression was associated with poor DFS ( p  < 0.05 for all). This finding was not fully supported by the data in the TCGA cohort, where high expression of  FOXM1  and  BRCA2  correlated with poor DFS. Conclusion: Low expression of  RAD52  correlated with decreased DFS in the Mannheim and the TCGA cohort. This effect was especially pronounced in the subset of patients who received ACBC, making it a promising indicator for response to ACBC on the level of gene expression.

international journal of molecular sciences

RNA Expression of DNA Damage Response Genes in Muscle-Invasive Bladder Cancer: Influence on Outcome and Response to Adjuvant Cisplatin-Based Chemotherapy