Abstract
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.
Highlights
Cancer is the leading cause of death in economically developed countries and the second leading cause of death in developing countries [1]
We have extensively reviewed literature and performed a meta-analysis based on all eligible case-control published data to evaluate the association between Exo1 K589E polymorphisms and cancer susceptibility
We found a significant association between Exo1 K589E polymorphism and cancer risk in all genetic models (Lys vs Glu: odds ratio (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)
Summary
Cancer is the leading cause of death in economically developed countries and the second leading cause of death in developing countries [1]. The burden of cancer is increasing in economically developing countries as a result of population aging and growth as well as, increasingly, an adoption of cancer-associated lifestyle choices including smoking. Primary prevention strategies aim to reduce incidence, the early detection as subclinical cancer cases are discovered, which increases the chance of a cure in early stage patients or prolongs their survival time. Most cancers are difficult to detect at their early stage, new markers for identifying high-risk populations as well as novel strategies for early detection are urgently needed. It has been suggested that susceptibility genes combining with environmental factors may be important in the development of cancer [3,4]
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