Functional FEN1 genetic variants contribute to risk of hepatocellular carcinoma, esophageal cancer, gastric cancer and colorectal cancer

Liu, Li; Zhou, Changchun; Zhou, Lixin; P, Li; Li, Dapeng; Zhang, Xiaojiao; Zhou, Mo; Kuang, Pengqun; Yuan, Qipeng; Song, Xianrang; Yang, Ming

doi:10.1093/carcin/bgr250

Cited by 85 publications

(90 citation statements)

References 13 publications

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“…The present study indicated that functional rs174538 and rs4246215 were significantly associated with an increased risk of cancer. These results are consistent to the findings in breast cancer, lung cancer, hepatocellular carcinoma, esophageal cancer, gastric cancer, colorectal cancer and glioma from different medical centers of China (18,(20)(21)(22), which confirmed our speculation that the functional genetic variants in the FEN1 gene may affect cancer risk as common factors.…”

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confidence: 92%

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

Ren

et al. 2015

Molecular and Clinical Oncology

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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...

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confidence: 92%

“…Four studies were review comments. Finally, 13 sub-studies from 4 studies on rs174538 and rs4246215 genotypes and cancer risk were identified (18,(20)(21)(22), including a total of 5,108 cancer cases and 6,382 case-free controls. The characteristics of the included studies are listed in Table I.…”

Section: Characteristics Of Studiesmentioning

confidence: 99%

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

Ren

et al. 2015

Molecular and Clinical Oncology

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“…In the current study, we have found the three metforminassociated metabolites significantly associated with two genes, FEN1 and C20orf94, which are involved in DNA repair (39,40). This may partly explain that metformin has been shown to influence the prevalence of different types of carcinoma, such as gastrointestinal cancers (39) and leukemia (40).…”

Section: Discussionsupporting

confidence: 48%

“…Beyond its common antihyperglycemic action and its effect in lowering LDL-C, metformin can potentially reduce the risk of cancer mortality and diminish the progression of cancer (38). In the current study, we have found the three metforminassociated metabolites significantly associated with two genes, FEN1 and C20orf94, which are involved in DNA repair (39,40). This may partly explain that metformin has been shown to influence the prevalence of different types of carcinoma, such as gastrointestinal cancers (39) and leukemia (40).…”

Section: Discussionmentioning

confidence: 48%

Effects of Metformin on Metabolite Profiles and LDL Cholesterol in Patients With Type 2 Diabetes

et al. 2015

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OBJECTIVEMetformin is used as a first-line oral treatment for type 2 diabetes (T2D). However, the underlying mechanism is not fully understood. Here, we aimed to comprehensively investigate the pleiotropic effects of metformin. RESEARCH DESIGN AND METHODSWe analyzed both metabolomic and genomic data of the population-based KORA cohort. To evaluate the effect of metformin treatment on metabolite concentrations, we quantified 131 metabolites in fasting serum samples and used multivariable linear regression models in three independent cross-sectional studies (n = 151 patients with T2D treated with metformin [mt-T2D]). Additionally, we used linear mixed-effect models to study the longitudinal KORA samples (n = 912) and performed mediation analyses to investigate the effects of metformin intake on blood lipid profiles. We combined genotyping data with the identified metforminassociated metabolites in KORA individuals (n = 1,809) and explored the underlying pathways. RESULTSWe found significantly lower (P < 5.0E-06) concentrations of three metabolites (acyl-alkyl phosphatidylcholines [PCs]) when comparing mt-T2D with four control groups who were not using glucose-lowering oral medication. These findings were controlled for conventional risk factors of T2D and replicated in two independent studies. Furthermore, we observed that the levels of these metabolites decreased significantly in patients after they started metformin treatment during 7 years' follow-up. The reduction of these metabolites was also associated with a lowered blood level of LDL cholesterol (LDL-C). Variations of these three metabolites were significantly associated with 17 genes (including FADS1 and FADS2) and controlled by AMPK, a metformin target. CONCLUSIONSOur results indicate that metformin intake activates AMPK and consequently suppresses FADS, which leads to reduced levels of the three acyl-alkyl PCs and LDL-C. Our findings suggest potential beneficial effects of metformin in the prevention of cardiovascular disease.Type 2 diabetes (T2D) is a chronic disease with diminished response to insulin and relative insulin deficiency (1). Patients with T2D mostly take metformin as first-line oral treatment to lower their glucose levels and to improve insulin sensitivity (2). Despite metformin's use as an antihyperglycemic agent for more than 50 years, its

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“…Part of the case-control set has been reported previously. 29 (ii) Beijing set (validation set 1): 250 ESCC patients from the Second Artillery General Hospital PLA (Beijing, China) and sexÀ and age-matched 2 Hospital. Controls were cancer-free individuals selected from a community cancer-screening program (3000 individuals) for early detection of cancer conducted in Huaian city during the same period as the patients were collected.…”

Section: Study Case-control Setsmentioning

confidence: 99%

Leukocyte telomere length‐related genetic variants in 1p34.2 and 14q21 loci contribute to the risk of esophageal squamous cell carcinoma

Shi

Sun²,

et al. 2012

Intl Journal of Cancer

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Short leukocyte telomere length has been associated with significantly increased risk of esophageal cancer. A previous genomewide association study demonstrated that four SNPs (rs398652 on 14q21, rs621559 on 1p34.2, rs6028466 on 20q11.22 and rs654128 on 6q22.1) were associated with leukocyte telomere length in Caucasians. However, the role of these genetic variants on esophageal squamous cell carcinoma (ESCC) susceptibility is still unknown. Therefore, we investigated whether these polymorphisms have impact on leukocyte telomere length and the risk of ESCC in Chinese. After measuring leukocyte telomere length of 550 healthy individuals, we observed that both rs621559 and rs398652 genetic variants are significantly associated with leukocyte telomere length. On the basis of analyzing 1550 ESCC patients and frequency-matched 1620 controls from 4 medical centers in China, we found that 0.71-fold decreased risk of ESCC is associated with the rs621559 AA genotype compared with the rs621559 GG genotype (p 5 5.9 3 10 26 ). We also detected a moderately increased OR for ESCC that was associated with the 14q21 rs398652 G allele (p 5 6.5 3 10 24 ). It has been shown that both rs621559 and rs398652 polymorphisms were significantly associated with ESCC risk in additive, recessive or dominant genetic models. Stratified analyses demonstrated that these associations were more pronounced in males. Our results highlight the complexity of genetic regulation of telomere length and further support the important role of telomere in carcinogenesis.

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Functional FEN1 genetic variants contribute to risk of hepatocellular carcinoma, esophageal cancer, gastric cancer and colorectal cancer

Cited by 85 publications

References 13 publications

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

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

Effects of Metformin on Metabolite Profiles and LDL Cholesterol in Patients With Type 2 Diabetes

Leukocyte telomere length‐related genetic variants in 1p34.2 and 14q21 loci contribute to the risk of esophageal squamous cell carcinoma

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