The Significance of Exo1 K589E Polymorphism on Cancer Susceptibility: Evidence Based on a Meta-Analysis

The exonuclease1 (Exo1) gene is a key component of mismatch repair (MMR) by resecting the damaged strand, which is the only exonuclease involved in the human MMR system. The gene product is a member of the RAD2 nuclease family and functions in DNA replication, repair and recombination. However, whether Exo1 is required to activate MMR-dependent DNA damage response (DDR) remains unknown, the conclusions of the Exo1 polymorphisms on cancer susceptibility studies were not consistent. We carried out a meta-analysis of 7 case-control studies to clarify the association between the Exo1 K589E polymorphism and cancer risk. Overall, a significant association of the Exo1 K589E polymorphism with cancer risk in all genetic models (Lys vs Glu: OR = 1.51, 95% CI: 1.39-1.99, P<0.01; Glu/Lys vs Glu/Glu: OR = 1.43, 95% CI: 1.28-1.60, P<0.01; Lys/Lys vs Glu/Glu: OR = 2.45, 95% CI: 1.90-3.17, P<0.01; Lys/Lys+Glu/Lys vs Glu/Glu: OR = 1.53, 95% CI: 1.38-1.71, P<0.01; Glu/Glu vs Glu/Lys+Lys/Lys: OR = 2.27, 95% CI: 1.79-2.89, P<0.01). In the stratified analysis by ethnicity, significantly increased risk was observed in Asian population (Lys vs Glu: OR = 1.53, 95% CI: 1.39-1.69, P<0.01; Glu/Lys vs Glu/Glu: OR = 1.50, 95% CI: 1.34-1.69, P<0.01; Lys/Lys vs Glu/Glu: OR = 2.48, 95% CI: 1.84-3.34, P<0.01; Lys/Lys+ Glu/Lys vs Glu/Glu: OR = 1.58, 95% CI: 1.41-1.78, P<0.01; Glu/Glu vs Glu/Lys+Lys/Lys: OR = 2.18, 95% CI: 1.62-2.93, P<0.01). Subgroup analysis based on smoking suggested Exo1 K589E polymorphism conferred significant risk among smokers (Lys/Lys+ Glu/Lys vs Glu/Glu: OR = 2.16, 95% CI: 1.77-2.63, P<0.01), but not in non-smokers (Lys/Lys+ Glu/Lys vs Glu/Glu: OR = 0.89, 95% CI: 0.64-1.24, P = 0.50). In conclusion, Exo1 K589E Lys allele may be used as a novel biomarker for cancer susceptibility, particularly in smokers.