MDM2 SNP309 and SNP285 Act as Negative Prognostic Markers for Non-small Cell Lung Cancer Adenocarcinoma Patients

Abstract

Objectives: Two functional polymorphisms in the MDM2 promoter region, SNP309T>G and SNP285G>C, have been shown to impact MDM2 expression and cancer risk. Currently available data on the prognostic value of MDM2 SNP309 in non-small cell lung cancer (NSCLC) is contradictory and unavailable for SNP285. The goal of this study was to clarify the role of these MDM2 SNPs in the outcome of NSCLC patients.Materials and Methods: In this study we genotyped SNP309 and SNP285 in 98 NSCLC adenocarcinoma patients and determined MDM2 mRNA and protein levels. In addition, we assessed the prognostic value of these common SNPs on overall and progression free survival, taking into account the TP53 status of the tumor.Results and Conclusion: We found that the SNP285C allele, but not the SNP309G allele, was significantly associated with increased MDM2 mRNA expression levels (p = 0.025). However, we did not observe an association with MDM2 protein levels for SNP285. The SNP309G allele was significantly associated with the presence of wild type TP53 (p = 0.047) and showed a strong trend towards increased MDM2 protein levels (p = 0.068). In addition, patients harboring the SNP309G allele showed a worse overall survival, but only in the presence of wild type TP53. The SNP285C allele was significantly associated with an early age of diagnosis and metastasis. Additionally, the SNP285C allele acted as an independent predictor for worse progression free survival (HR = 3.97; 95% CI = 1.51 - 10.42; p = 0.005).Our data showed that both SNP309 (in the presence of wild type TP53) and SNP285 act as negative prognostic markers for NSCLC patients, implicating a prominent role for these variants in the outcome of these patients.

Association of the MDM2 SNP285 and SNP309 Genetic Variants with the Risk, Age at Onset and Prognosis of Breast Cancer in Central European Women: A Hospital-Based Case-Control Study

“…Interestingly, amplification of MDM2 , another clinically relevant mechanism in carcinogenesis to increase MDM2 and decrease p53 expression, was also found to be associated with a reduced rate of TP53 mutation [10,13,54]. Like in the present study, a reduced rate of TP53 mutations in carriers of the SNP309G allele has been reported for non-small cell lung cancer [55], hepatocellular carcinoma [35], and bladder cancer [56]. In contrast, no significant association was found in oral cancer, pancreatic cancer, and two studies of colorectal cancer [57,58,59,60].…”

“…The association of SNP285 with survival has previously been analyzed in two lung cancer studies. One study found no association, whereas the other study found an association of the SNP285GC genotype with a worse progression-free survival compared to the GG genotype, but no association with the overall survival [32,55].…”

Towards Prognostic Profiling of Non-Small Cell Lung Cancer: New Perspectives on the Relevance of Polo-Like Kinase 1 Expression, the TP53 Mutation Status and Hypoxia

“…RNA was extracted using the RNeasy FFPE isolation kit (Qiagen, Venlo, The Netherlands), according to the manufacturers' instructions. RNA concentrations and purity were measured as described previously 27 . Subsequently, reverse transcription was performed using the High Capacity RNA-to-cDNA kit (ThermoFisher Scientific, Nepean, Canada) and real-time PCR was performed using the TaqMan Gene Expression Master Mix on a LightCycler480 instrument (Roche, Vilvoorde, Belgium).…”

“…DNA isolation was performed using the QIAmp DNA FFPE tissue kit (Qiagen), according to the manufacturer's instructions. DNA concentrations and purity were determined as described previously 27 . Subsequently, TP53 next generation sequencing was performed on 69 genomic tumor DNA samples using the commercially available TP53 MASTR TM with MID for Illumina Miseq kit (Multiplicom, Niel, Belgium), according to the manufacturer's instructions.…”

The 40bp Indel Polymorphism rs150550023 in the MDM2 Promoter is Associated with Intriguing Shifts in Gene Expression in the p53-MDM2 Regulatory Hub

“…MDM2 amplification and overexpression occurs mostly in a mutually exclusive manner with TP53 mutation, indicating that it may be one important of presumably several mechanisms of aberrant inactivation of p53 function in TP53 wildtype tumors [ 8 , 9 , 16 ]. Like MDM2 amplification, albeit less pronounced, the G-allele of SNP309 (rs2279744) in MDM2 promoter P2 was also found associated with increased MDM2 expression and a reduced rate of TP53 mutation [ 17 , 18 , 19 , 20 , 21 , 22 , 23 ]. Moreover, most studies in Asian, but not in Caucasian populations found an association of the G-allele of SNP309 with an increased cancer risk [ 24 , 25 , 26 ].…”