The association between RFC1 G80A polymorphism and cancer susceptibility: Evidence from 33 studies

Aberrant folate metabolism is closely related to tumorigenesis. Genetic variations in the Reduced folate carrier 1 (RFC1) may alter the progress of folate metabolism, and thereby cause the initiation and progress of the cancer. Considerable studies have performed to investigate the association between RFC1 G80A (rs1051266) polymorphism and cancer susceptibility, but the conclusions were conflicting. Therefore, we conducted a meta-analysis to reevaluate the association of RFC1 G80A polymorphism with cancer risk. PubMed and EMBASE were searched for eligible studies. The association of RFC1 G80A polymorphism and cancer risk was evaluated by the pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs). The significant association was found between RFC1 G80A polymorphism and hematological malignance susceptibility (A vs. G: OR=1.11, 95% CI=1.003-1.23, P=0.045; GA vs. GG: OR=1.18, 95% CI=1.06-1.31, P=0.002; AA+GA vs. GG: OR=1.18, 95% CI=1.07-1.29, P=0.001). Stratified analysis by ethnicity indicated that the association became more prominent among Caucasians (GA vs. GG: OR=1.28, 95% CI=1.12-1.45, P<0.001; AA+GA vs. GG: OR=1.21, 95% CI=1.08-1.36, P=0.001). In term of the cancer type, this polymorphism significantly increased the risk of acute lymphoblast leukemia (GA vs. GG: OR=1.13, 95% CI=1.001-1.28, P=0.048; AA+GA vs. GG: OR=1.28, 95% CI=1.13-1.46, P<0.001) and acute myeloid leukemia (GA vs. GG: OR=2.57, 95% CI=1.37-4.85, P=0.003). No significant association between RFC1 G80A polymorphism and overall solid cancer risk was observed, but a protective association with digestive cancer risk was found (GA vs. GG: OR=0.89, 95% CI= 0.81-0.99, P=0.030). The comprehensive meta-analysis encouraged the notion that RFC1 G80A polymorphism may play an important role in hematopoietic system malignance. These findings need further validation in the large multicenter investigations.