Differential Expression Of FEN1 Caused By DNA Genetic And Epigenetic Changes Is Associated With Multiple Cancers

Background & Aims: Flap endonuclease 1 (FEN1), involved in many DNA metabolic pathways, plays an essential role in maintaining genome integrity and cancer development. The genetic and epigenetic changes of FEN1 gene might contribute to differential FEN1 expression and, thus, be associated with individual susceptibility to cancer development and poor prognosis. This study sought to identify single nucleotide polymorphisms (SNPs) in the FEN1 gene and aberrant methylation of its promoter CpG islands and evaluated their effects on tumor development and progression.Methods: DNA samples from 30 individuals were sequenced to search for SNPs in FEN1, and the function of the SNPs was investigated by a series of biochemical assays. The association between the FEN1 genotypes and the In-transformed Olive tail moment (Olive TM) values were tested in coke-oven workers, and the association between the genotypes and lung cancer susceptibility were examined in a case-control panel consisting of 1,013 lung cancer patients and 1,131 controls. The odds ratios and their 95% confidence intervals were estimated by logistic regression. The promoter methylation was identified by sequencing of sodium bisulfite-treated DNA and mRNA levels were determined by quantitative real-time RT-PCR. FEN1 expression was detected in BD Clontech^TM Cancer Profiling Array I and a Cybrdi^TM Breast Carcinoma Progression Tissue Array.Results: Two SNPs (-69G/A and 4150G/T) were identified and the -69G and 4150G alleles were associated with reduced expression of FEN1 in vitro and in vivo. The higher In-transformed Olive TM values of coke-oven workers and significantly increased risks for developing lung cancer were associated with the FEN1 -69G or 4150G allele compared with the -69A or 4150T allele, respectively. A multiplicative joint effect between smoking and FEN1 polymorphisms in intensifying lung cancer risk was detected. FEN1 mRNA was overexpressed in multiple cancers compared with matched normal tissue. In breast cancer, FEN1 expression was inversively correlated with the degree of tumor differentiation. Moreover, we identified two CpG islands in the FEN1 promoter region and showed that hypomethylation of CpG island2 is important in regulating overexpression of the FEN1 gene in tumors.Conclusion: Functional SNPs in FEN1 are associated with susceptibility to DNA damage and lung cancer development, and elevated FEN 1 expression due to the aberrant promoter methylation may be associated with cancer progression.