The Ability of Polymorphisms in DNA Repair Enzymes to Predict Clinical Outcome in Colorectal Cancer Patients.

Background: Genomic polymorphisms of DNA repair enzymes-excision repair cross complementation group 1 (ERCC1), excision repair cross complementation group 2 (ERCC2), and X-ray repair cross complementation group 1 (XRCC1) correlate with survival and therapeutic responses in colorectal cancer (CRC) patients. Therefore, the present study examined the frequency of ERCC1 C118T, ERCC2 Lys751Gln, and XRCC1 Arg399Gln polymorphisms and their prognostic and predictive values in CRC patients. Method: In this retrospective study, a total of 143 CRC patients were evaluated for these polymorphisms by PCR-RFLP. Results: The majority of the patients showed heterozygous C/T (56%) compared to wild type C/C (29%) and variant T/T (15%) genotypes for ERCC1 C118T polymorphism. ERCC2 Lys751Gln polymorphism showed wild type A/A (44%), heterozygous A/C (40%), and variant C/C genotypes (16%). The frequency of XRCC1 Arg399Gln polymorphism was 48% (wild type G/G), 42% (heterozygous G/A), and 10% (variant A/A). The relapse-free survival (RFS) significantly decreased in patients with ERCC1 118 C/C wild type genotype in the subgroups of patients with advanced stage and colon cancer; however, variant T/T genotype correlated with reduced overall survival (OS) in patients treated with combined drug 5-FU/Oxaliplatin. Taken together, in CRC patients and patients treated with 5-FU/Oxaliplatin, ERCC2 Lys751Gln A/A wild type genotype led to significantly unfavorable clinical outcomes. However, XRCC1 Arg399Gln polymorphism did not show any significant association with prognosis. Additionally, on analyzing combined effect of ERCC1 and ERCC2 polymorphisms, a significant reduced OS in patients with both unfavorable genotypes (ERCC1: C/C and ERCC2: A/A) was found. Furthermore, in the subgroup of patients treated with 5-FU/Oxaliplatin, RFS and OS significantly decreased in patients with both unfavorable genotypes (ERCC1: T/T and ERCC2: A/A). Conclusion: The significant relationship of ERCC1 C118T and ERCC2 Lys751Gln polymorphisms with prognosis and treatment response reflects the vital role of these molecules as prognostic and predictive markers in patients with CRC. Additionally, the combined evaluation of ERCC1 and ERCC2 polymorphisms might identify high risk CRC patients with poor prognosis. [ABSTRACT FROM AUTHOR]