The rs1550117 A&gt;G variant in DNMT3A gene promoter significantly increases non-small cell lung cancer susceptibility in a Han Chinese population

Jingdong Wang,Bifeng Chen,Jingli Zhang,Jiankun Zhang,Xianhong Feng,Zhou Li,Chade Li,Liang Tang,Fengting Wan

doi:10.18632/oncotarget.15625

The rs1550117 A>G variant in DNMT3A gene promoter significantly increases non-small cell lung cancer susceptibility in a Han Chinese population

Jingdong Wang, Bifeng Chen + Show 7 more

Open Access

https://doi.org/10.18632/oncotarget.15625

Copy DOI

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

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

Methods

Results

Conclusion