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

2021 ◽  
Vol 22 (8) ◽  
pp. 4188
Author(s):  
Jonas Herrmann ◽  
Helena Schmidt ◽  
Katja Nitschke ◽  
Cleo-Aron Weis ◽  
Philipp Nuhn ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Damage ◽  
Bladder Cancer ◽  
Dna Damage Response ◽  
Invasive Bladder Cancer ◽  
Rna Expression ◽  
Muscle Invasive Bladder Cancer ◽  
Damage Response ◽  
Muscle Invasive ◽  
Low Expression

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.

scholarly journals MP45-12 PROGNOSTIC VALUE OF DNA DAMAGE RESPONSE RELATED PROTEINS IN NON-MUSCLE INVASIVE BLADDER CANCER

2016 ◽  
Vol 195 (4S) ◽  
Author(s):  
Albert Frances ◽  
Nuria Juanpere ◽  
Judith Penafiel ◽  
Gloria Nohales ◽  
Cristina Camara ◽  
...  
Keyword(s):  
Dna Damage ◽  
Bladder Cancer ◽  
Dna Damage Response ◽  
Prognostic Value ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
Damage Response ◽  
Muscle Invasive ◽  
Related Proteins

scholarly journals Gene Expression Analyses in Non Muscle Invasive Bladder Cancer Reveals a Role for Alternative Splicing and Tp53 Status

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Marta Dueñas ◽  
Andrés Pérez-Figueroa ◽  
Carla Oliveira ◽  
Cristian Suárez-Cabrera ◽  
Abel Sousa ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bladder Cancer ◽  
Alternative Splicing ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
Gene Expression Analyses ◽  
Muscle Invasive ◽  
Tp53 Status

scholarly journals APOBEC-mediated mutagenesis in urothelial carcinoma is associated with improved survival, mutations in DNA damage response genes, and immune response

2017 ◽  
Author(s):  
Alexander P. Glaser ◽  
Damiano Fantini ◽  
Kalen J. Rimar ◽  
Joshua J. Meeks
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Dna Damage ◽  
Bladder Cancer ◽  
Urothelial Carcinoma ◽  
Dna Damage Response ◽  
Molecular Subtype ◽  
Regulatory Genes ◽  
Enrichment Score ◽  
Damage Response

AbstractBackgroundThe APOBEC family of enzymes is responsible for a mutation signature characterized by a TCW>T/G mutation. APOBEC-mediated mutagenesis is implicated in a wide variety of tumors, including bladder cancer. In this study, we explore the APOBEC mutational signature in bladder cancer and the relationship with specific mutations, molecular subtype, gene expression, and survival. We hypothesized that tumors with high levels of APOBEC-mediated mutagenesis would be enriched for mutations in DNA damage response genes and associated with higher expression of genes related to activation of the immune system.MethodsGene expression (n=408) and mutational (n=395) data from the Cancer Genome Atlas (TCGA) bladder urothelial carcinoma provisional dataset was utilized for analysis. Tumors were split into “APOBEC-high” and “APOBEC-low” tumors based on APOBEC enrichment score. Analysis was performed with R.FindingsPatients with APOBEC-high tumors have better overall survival compared to those with APOBEC-low tumors (38.2 vs 18.5 months, p=0.005). Tumors enriched for APOBEC mutagenesis are more likely to have mutations in DNA damage response genes (TP53, ATR, BRCA2), and chromatin regulatory genes (MLL, MLL3), while APOBEC-low tumors are more likely to have mutations inFGFR3andKRAS. APOBEC3AandAPOBEC3Bexpression correlates with total mutational burden, regardless of bladder tumor molecular subtype. APOBEC mutagenesis and enrichment is associated with increased expression of immune-related genes, including interferon signaling.InterpretationTumors enriched for APOBEC mutagenesis are more likely to have mutations in DNA damage response genes and chromatin regulatory genes, potentially providing more single-strand DNA substrate forAPOBEC3AandAPOBEC3B, leading to a hypermutational phenotype and the subsequent immune response.HighlightsABPOEC enzymes, particularlyAPOBEC3AandAPOBEC3B, are responsible for the predominant pattern of mutagenesis in bladder cancerTumors enriched for APOBEC-mediated mutagenesis are more likely to have mutations in DNA damage response genes and chromatin regulatory genes, while tumors not enriched for APOBEC-mediated mutagenesis are more likely to have mutations inKRASandFGFR3APOBEC enrichment is associated with upregulation of genes involved in the immune response

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