Abstract

In this study, we conducted a case-control study to explore the association between rs1550117 A>G variant of DNMT3A gene promoter and non-small cell lung cancer (NSCLC) susceptibility in a Han Chinese population. The genotyping of rs1550117 A>G variant was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and confirmed by sequencing. Allele G of rs1550117 was associated with an increased risk of NSCLC. Moreover, individuals carrying the GG genotypes had a higher risk to develop NSCLC than the AA and GA genotype carriers. Further stratified analysis showed that rs1550117 A>G was significantly related to age (> 60 years), male, smoking and drinking. In vivo detection of DNMT3A mRNA levels in NSCLC tissues and in vitro luciferase assays consistently showed that the allele G significantly decreased DNMT3A transcription. Additional functional analysis revealed that the increased binding affinity of transcription repressor SP1, which was associated with allele G of rs1550117, led to the significant decreased expression of DNMT3A. Collectively, our results propose a suppression role of DNMT3A in NSCLC development and emphasize the dual roles of DNMT3A in tumorigenesis.

Highlights

  • Lung cancer has been the leading cancer diagnosed and cause of cancer death for many years in China, especially in Hubei province with a high incidence and mortality rate [1, 2]

  • The genotype frequencies of rs1550117 A>G variant were in agreement with Hardy-Weinberg equilibrium (HWE) in normal controls (p = 0.537), suggesting the enrolled control subjects were representative

  • The G allele frequency was significantly higher among non-small cell lung cancer (NSCLC) patients than normal controls (p = 0.001, OR = 1.36, 95%confidence intervals (CIs) = 1.18–1.71), indicating allele G was associated with an increased risk of NSCLC

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Summary

Introduction

Lung cancer has been the leading cancer diagnosed and cause of cancer death for many years in China, especially in Hubei province with a high incidence and mortality rate [1, 2]. Surgical resection has been an efficient curative treatment for lung cancer patients in earlier stage [2]. Most lung patients are diagnosed in stage IIIB/IV, during which period the tumor are unresectable anymore. Aberrant DNA methylation patterns have been found in most human cancers, including NSCLC [5]. As a de novo DNA methyltransferase, DNMT3A contributes to the establishment of genomic DNA methylation patterns [6], indicating that abnormal DNMT3A expression may be responsible for the aberrant DNA methylation in carcinogenesis. Identification of functional www.impactjournals.com/oncotarget variants in DNMT3A gene and analysis of their effects may lead to a better understanding of their impact on DNMT3A gene expression and individual susceptibility to cancer

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