Early onset lung cancer, cigarette smoking and the SNP309 of the murine double minute-2 (MDM2) gene

Kirstin Mittelstraß ,Eckart Meese,Dagmar Taeuscher,Bettina Jilge,Thomas Illig,Heike Bickeboeller,Angela Risch,Maria Degen,Andreas Groeschel,Wiebke Sauter,Maria Timofeeva,Christine Schmidt,Wilhelm Schmidt,Hendrik Dienemann,Albert Rosenberger,You-Dschun Ko,Karl Haeußinger,Norman Klopp,Karsten Grosse Kreymborg,Gabi Woelke,Heinz‐Erich Wichmann ,Gert Hoeffken ,M Cebulla ,Jenny Chang‐Claude ,P Drings ,Gerhard W Sybrecht ,H Morr

doi:10.1186/1471-2407-8-113

Abstract

The polymorphism SNP309 (rs2279744) in the promoter region of the MDM2 gene has been shown to alter protein expression and may play a role in the susceptibility to lung cancer. The MDM2 protein is a key inhibitor of p53 and several mechanisms of MDM2/p53 interactions are presently known: modulating DNA-repair, cell-cycle control, cell growth and apoptosis.We used 635 Caucasian patients diagnosed with lung cancer before 51 years of age and 1300 healthy gender and age frequency matched population Caucasian controls to investigate the association between the MDM2 SNP309 and the risk of developing early onset lung cancer. Conditional logistic models were applied to assess the genotype-phenotype association, adjusted for smoking.Compared to the GG genotype, the adjusted ORs for the TG and TT genotype were 0.9 (95% CI: 0.7–1.5) and 1.0 (95% CI: 0.7–1.5), respectively. Also no association was found for histological subtypes of lung cancer. The strength of this study is that within young cases the genetic component to develop lung cancer may be greater. Our results indicate that the MDM2 SNP309 is not significantly associated with lung carcinogenesis but point towards gender-specific differences.

Highlights

Human cells have developed a complex system to protect themselves from genotoxic damage where the p53 tumor suppressor gene plays an important role in protecting against such insults by serving as an integrator of the signals produced by DNA damage
Applying the propensity score approach we found no agreement between the true and the assigned membership to a case-sample
Given that lung cancer is a result of gene-environmental interaction, the genetic component may be a strong risk factor among early onset lung cancer patients

Summary

Introduction

Human cells have developed a complex system to protect themselves from genotoxic damage where the p53 tumor suppressor gene plays an important role in protecting against such insults by serving as an integrator of the signals produced by DNA damage. The MDM2 protein inhibits p53 transactivation activity and promotes its export from the nucleus by binding to the transcriptional activation domain of p53 [1] and acts as an ubiquitin ligase upon p53 pushing fast degradation of the suppressor [2,3]. A SNP (SNP309, G2580T) at the intronic p53response promoter of MDM2 was identified and associated with altered Sp1 binding affinity and expression levels of MDM2 RNA and protein [4]. Contradictory results were reported regarding the MDM2 SNP309 association with lung cancer [5,6,7,8]. Our study is the first report on a large German case-control study of young lung cancer patients (age of onset < 51 years) investigating the MDM2 SNP 309

Methods

Results

Discussion

Conclusion