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

Abstract

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.

Differential expression of DNA damage repair genes after chemoradiotherapy and inhibition rate in different bladder cancer cells

“…The expression levels of BRCA1 and RBBP8 were not significantly correlated with the OS of patients with bladder cancer ( Figure 2 ). However, BRCA1 and RBBP8 were correlated with the efficacy of cisplatin-based neoadjuvant chemotherapy, which was more significantly associated with poor disease-free survival ( 11 ). BRCA1 mRNA expression was related to the outcome of neoadjuvant cisplatin-based chemotherapy in bladder cancer; the median survival was 168 months for patients with low expression levels and 34 months for patients with high expression levels ( 12 ).…”

Prediction of immune infiltration and prognosis for patients with urothelial bladder cancer based on the DNA damage repair-related genes signature

“…Wang et al found that the DDR key gene BRCA1 could be inhibited by XPC inhibition in BLCA, which could lead to increased chromosomal instability and maintaining cisplatin-induced DNA damage [ 68 ]. Moreover, DDR-related genes have been found to be able to effectively predict disease-free survival for muscle-invasive BLCA [ 69 ]. The same effect has also been found in Doxorubicin, Mitomycin and Camptothecin, which are mainly dependent on the DNA-cytotoxicity.…”

Biomarkers for Early Detection of Cancer: Molecular Aspects

“…On the other hand, mutations in DNA damage response genes (DDRG) can predict the response to cisplatin-based chemotherapy. Herrmann et al [ 10 ] examined the value of RNA expression levels of several key DDRGs ( BCL2 , BRCA1 , BRCA2 , ERCC2 , ERCC6 , FOXM1 , RAD50 , RAD51 , and RAD52 ) in patients with muscle-invasive bladder cancer and validated these with The Cancer Genome Atlas (TCGA). It was determined that the low expression of RAD52 correlated with decreased disease-free survival in patients, which was validated by TCGA.…”