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 ۱ (ERCC۱), excision repair cross complementation group ۲ (ERCC۲), and X-ray repair cross complementation group ۱ (XRCC۱) correlate with survival and therapeutic responses in colorectal cancer (CRC) patients. Therefore, the present study examined the frequency of ERCC۱ C۱۱۸T, ERCC۲ Lys۷۵۱Gln, and XRCC۱ Arg۳۹۹Gln polymorphisms and their prognostic and predictive values in CRC patients. Method: In this retrospective study, a total of ۱۴۳ CRC patients were evaluated for these polymorphisms by PCR-RFLP. Results: The majority of the patients showed heterozygous C/T (۵۶%) compared to wild type C/C (۲۹%) and variant T/T (۱۵%) genotypes for ERCC۱ C۱۱۸T polymorphism. ERCC۲ Lys۷۵۱Gln polymorphism showed wild type A/A (۴۴%), heterozygous A/C (۴۰%), and variant C/C genotypes (۱۶%). The frequency of XRCC۱ Arg۳۹۹Gln polymorphism was ۴۸% (wild type G/G), ۴۲% (heterozygous G/A), and ۱۰% (variant A/A). The relapse-free survival (RFS) significantly decreased in patients with ERCC۱ ۱۱۸ 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 ۵-FU/Oxaliplatin. Taken together, in CRC patients and patients treated with ۵-FU/Oxaliplatin, ERCC۲ Lys۷۵۱Gln A/A wild type genotype led to significantly unfavorable clinical outcomes. However, XRCC۱ Arg۳۹۹Gln polymorphism did not show any significant association with prognosis. Additionally, on analyzing combined effect of ERCC۱ and ERCC۲ polymorphisms, a significant reduced OS in patients with both unfavorable genotypes (ERCC۱: C/C and ERCC۲: A/A) was found. Furthermore, in the subgroup of patients treated with ۵-FU/Oxaliplatin, RFS and OS significantly decreased in patients with both unfavorable genotypes (ERCC۱: T/T and ERCC۲: A/A). Conclusion: The significant relationship of ERCC۱ C۱۱۸T and ERCC۲ Lys۷۵۱Gln 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 ERCC۱ and ERCC۲ polymorphisms might identify high risk CRC patients with poor prognosis.

کلیدواژه ها:

ERCC۱ ، ERCC۲ ، XRCC۱ ، Polymorphism ، Colorectal cancer ، Prognosis