Polymorphism Of ERCC1 C118T Gene And Chemosensitivity Of Platinum In Advanced Bladder Cancer

Objective:Bladder cancer (BC) is the most common malignancy of the urinary tract.Gemcitabine combined with cisplatin (GC) have been used as the standard first-line regime, and has been shown to improve the overall survival and quality of life of BC patients. However, less than 50% patients were found to be responsive to chemotherapy.Therefore, it is important to find new biomarkers to accurately predict disease prognosis and patient responses to therapies. Platinum compounds including cisplatin are heavy metal complexes that form adducts and covalent cross-links between the two DNA strands, thus effectively blocking DNA replication and transcription. Excision repair cross-complementation group 1 (ERCC1), a crucial complex in the nucleotide excision repair (NER) pathways, plays a pivotal role in DNA damage recognition and removal of damaged nucleotides. It has been shown that high expression of the ERCC1 gene is associated with poor clinical outcome following cisplatin-based adjuvant chemotherapy for locally advanced bladder cancer. However, there has been no report on the association between the ERCC1 codon Cl 18T polymorphism and the response rate in bladder cancer patients treated with platinum-based chemotherapy. Therefore, we performed this retrospective study in order to determine whether ERCC1 codon Cl 18T polymorphism can be used as a novel biomarker to predict BC prognosis and treatment responses.Material and Methods:A total of 41 eligible patients histologically confirmed as having stage IV muscle-invasive transitional cell carcinoma of the bladder were treated with platinum-based chemotherapy for 2-6 cycles. The genotypes of patients were determined by PCR amplification of genomic DNA followed by restriction enzyme digestion (PCR-RFLP). Positive responses were categorized as complete and partial responses (CR and PR).In addition, progression-free survival (PFS) and overall survival (OS) were also determined as indicators of long-term outcomes.Results:The genotype frequencies of C/C, C/T and T/T genotypes were 56.1%, 34.1%, and 9.8%, respectively. Positive response was observed in 14 patients (34.1%), while 27 patients (65.9%) were negative responders. As compared with individuals carrying the C/T and T/T genotypes, those with the C/C genotype had significantly improved short-term treatment responses (P=0.018). The median PFS of patients carrying the C/C genotype was 6.3 months, while that of patients with C/T and T/T genotypes was 4.2 months (P=0.023). Moreover, the median OS for patients carrying the C/C genotype was also longer as compared with that of patients carrying C/T and T/T (11.7 months vs.8.5 months, P=0.040).Conclusions:Our results indicated that the ERCC1 codonl 18 polymorphism may have predictive potential for chemotherapy treatment responses in late-stage bladder cancer patients.