Flap endonuclease 1 polymorphisms (rs174538 and rs4246215) contribute to an increased cancer risk: Evidence from a meta-analysis

Abstract

Abstract. Flap endonuclease-1 (FEN1) is a key factor during the maintenance of genomic stability and protection against tumorigenesis. Since the identification of functional polymorphisms of FEN1 (rs174538 and rs4246215), numerous studies have evaluated the association between the two single-nucleotide polymorphisms and cancer risk. To derive a more precise estimation, a meta-analysis was performed on the association between the FEN1 polymorphisms (rs174538 and rs4246215) and cancer risk. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to estimate the strength of the associations. Thirteen case-control studies, including 5,108 cases and 6,382 case-free controls, were identified. For rs174538, individuals with the GG or GA genotype had an increased risk of cancer when compared to the -69AA genotype (AA vs. GG: OR, 1.85; 95% CI, 1.65-2.08; P<0.00001; AA vs. GA: OR, 1.43; 95% CI, 1.27-1.60; P<0.00001; AA vs. GG+GA: OR, 1.28; 95% CI, 1.16-1.42; P<0.00001). For rs4246215, similar results were identified, as the GG or GT genotype was significantly associated with the increased cancer risk when compared to TT (TT vs. GG: OR, 1.71; 95% CI, 1.52-1.92; P<0.00001; TT vs. GT: OR, 1.34; 95% CI, 1.20-1.50; P<0.00001; TT vs. GG+GT: OR, 1.50; 95% CI, 1.35-1.67; P<0.00001). The present meta-analysis indicated that FEN1 rs174538 and rs4246215 polymorphisms may contribute to an increased risk of cancer. IntroductionFlap endonuclease 1 (FEN1) is a versatile, structure specific and multifunctional nuclease involved in DNA replication and repair (1,2). Human FEN1, which is the archetypal member of the Rad2 nuclease family (3,4), is located on chromosome 11q12 and consists of two exons and one intron. FEN1 efficiently removed the 5'-flaps generated by Polδ/ε during repair synthesis of long-patch base-excision repair (LP-BER) and removed primers during lagging-strand DNA synthesis and Okazaki fragment processing (3,5,6). Furthermore, FEN1 can be stimulated to promote apoptotic DNA fragmentation following apoptotic stimuli, acting as a 5' exonuclease (1) and a gap-dependent endonuclease (7,8), as reported via its ability to participate in multiple protein-protein interactions. Thus far, >30 FEN1-interacting proteins have been identified (2). Of these FEN1 interaction partners, proliferating cell nuclear antigen (PCNA), which was initially identified as a replication accessory protein, accompanies FEN1 in all FEN1-involved DNA metabolic pathways except for the apoptotic DNA fragmentation pathway, suggesting a critical role of the FEN1/PCNA interaction in regulating LP-BER (9). A tumor suppressor function for FEN1 has been shown in preclinical models (10-14). Therefore, FEN1 has been considered as a key factor during maintenance of genomic stability and protecting against carcinogenesis.However, being a multifunctional factor, mutation of FEN1 has been suggested to cause genomic instability and predisposition to cancer. The functional impairment of yeast RAD27 (the homolog of mammalian FEN1) leads to a marked increase in th...

Flap endonuclease‐1 rs174538 G>A polymorphisms are associated with the risk of esophageal cancer in a Chinese population

“…Previous studies have shown that the FEN1 rs174538G>A SNP located in the promoter region causes increased promoter activity. These findings indicate that naturally occurring genetic polymorphisms in the regulation regions of cancer‐related genes may represent a significant potential factor for cancer risk . These results are also consistent with findings in hepatocellular carcinoma, and breast, lung, esophageal, gastric, and colorectal cancers in centers across China …”

FEN1 −69G>A and +4150G>T polymorphisms and breast cancer risk

“…The findings revealed that subjects with -69A or +4150T alleles of the FEN1 gene were associated with a decreased risk of cancer. A recent meta-analysis designated that FEN1 rs174538 and rs4246215 polymorphisms may contribute to an increased risk of cancer (28). The findings indicated that the GG or GA genotype increased the risk of cancer when compared to the rs174538 AA genotype.…”

Base Excision Repair Gene Polymorphisms and Wilms Tumor Susceptibility

“…Association study with 1840 lung cancer patients and 1958 controls further revealed that these two FEN1 SNPs conferred genetic susceptibility to lung cancer [ 49 ]. Moreover, some evidence was further observed to consolidate the contribution of the rs174538 and rs4246215 to the risk of different types of cancer [ 25 , 36 , 37 , 39 ]. Especially, these two SNPs were shown to decrease breast cancer risk in Chinese [ 25 ]and Iran [ 37 ] populations.…”