Bladder Cancer: Basic Research IModerated Poster561 GENETIC ALTERATIONS OF THE KEAP1/NRF2 PATHWAY IN TRANSITIONAL CELL CARCINOMAS OF THE BLADDER
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INTRODUCTION AND OBJECTIVES
The KEAP1/NRF2 pathway is a master regulator of several redox-sensitive genes implicated in prevention of chemically induced carcinomas of several origins. A critical role of KEAP1/NRF2 dysfunction has been discussed for tobacco smoke induced carcinogenesis in bladder cancer. Therefore we examined transitional cell carcinomas of the bladder for allelic loss in the KEAP1 gene.
METHODS
Primary tumors of 110 patients who underwent transurethral resection of transitional cell carcinomas of the bladder were studied for loss of heterozygosity in three microsatellite loci surrounding the KEAP1 gene in a multiplex PCR reaction with fluorescence-labeled primers. Evaluation of results was done on an ABI310 Genetic Analyzer with the Genemapper software. Results were compared to clinical data.
RESULTS
Loss of heterozygosity was found in 34 of 110 examined tumors (31%). 18 carcinomas showed allelic loss in one microsatellite locus, 15 in 2 loci and 1 in all three microsatellite loci. 17 of 36 muscle invasive carcinomas showed loss of heterozygosity in at least 1 microsatellite locus (47%). Muscle invasive carcinomas were characterized by a significant higher frequency of allelic loss compared to non muscle invasive carcinomas (p=0.01). Allelic loss in the KEAP1 gene was significantly
CONCLUSIONS
Allelic loss in the KEAP1 gene is a frequent event in transitional cell carcinomas of the bladder. The significant association of allelic loss with muscle invasive growth and metastasis suggests that loss of KEAP1 function followed by a constitutive activation NRF2-mediated gene expression leads to an improved survival and more aggressive behavior of cancer cells.
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