Prognostic potential of the <i><scp>MDM</scp>2</i> 309T&gt;G polymorphism in stage I lung adenocarcinoma

Enokida, Yasuaki; Shimizu, Kimihiro; Abe, Jun; Kakegawa, Seiichi; Takase, Yoshiaki; Kaira, Kyoichi; Yashima, Hideaki; Araki, Takuya; Nakazawa, Shozo; Ohtaki, Yoichi; Nagashima, Toshiteru; Lezhava, Alexander; Usui, Kengo; Ishikawa, Toshihisa; Hayashizaki, Yoshihide; Takeyoshi, Izumi

doi:10.1002/cam4.750

Cited by 6 publications

(4 citation statements)

References 33 publications

(54 reference statements)

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“…Only one previous study took the p53 status into account, limited to stage I tumors, showing a better OS in wild type p53 patients harboring the SNP309TG or SNP309GG genotype 15 . Recently, Enokida et al reported similar results, showing that the SNP309TT genotype was predictive for poorer survival in stage I patients, without taking the p53 status into account 16 . These data seem inconsistent with our results in stage 1 tumors (data not shown).…”

Section: Discussionmentioning

confidence: 78%

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

et al. 2017

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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.

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Section: Discussionmentioning

confidence: 78%

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

et al. 2017

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“…There was, however, no effect of either polymorphism on age at diagnosis of LC or on overall survival [ 47 ]. Enokida et al published a case-control study showing gene MDM2 T/T, T/G, G/G polymorphic variants frequencies in samples to be 21.1%, 49.7%, and 30.2%, respectively [ 48 ]. Our study polymorphisms frequencies of MDM2 c.-5+309 G>T gene T/T, T/G, G/G showed that T/T polymorphic variant dominates and frequencies are 50.00%, 43.48%, 6.52%, respectively.…”

Section: Discussionmentioning

confidence: 99%

Individual and combined effect ofTP53, MDM2, MDM4, MTHFR, CCR5,andCASP8gene polymorphisms in lung cancer

et al. 2017

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Lung cancer (LC) is the second common and with the highest mortality oncological disease. Specific biomarkers for its diagnostics, treatment, and prognosis are still under the investigations. Aim of our study was to evaluate the relationship between the polymorphisms of TP53 pathway genes TP53, MDM2, MDM4, the polymorphisms of HPV-associated genes MTHFR, CASP8, CCR5, and HPV infection with survival of LC patients. SNPs were genotyped using PCR-RFLP. qRT-PCR was used to detect, identify, and quantify HPV. No statistically significant differences were detected between individual SNPs and patient survival with stage I-IV LC. Cluster analysis of SNPs in genes MDM4 A/A, CCR5 wt/Δ32, MTHFR C/T, MDM2 T/T showed possible association with the worse survival. Patients who were diagnosed with C/T polymorphic variant of gene MTHFR tend not to survive stage III-IV LC (P = .12). There is a tendency between MDM2 gene T/T variant and worse survival of patients diagnosed with late stage LC (P = .11). HPV infection is very rear among LC patients (3 of 92). Overall, there is a link, although statistically insignificant, between specific SNPs and LC patient survival frequency and time, meanwhile the combination of specific SNPs showed a statistically significant measure. In conclusion, we determined statistically significant (P = .04) link between the poor survival of LC patients after surgery and the combination of polymorphic variants C/T of the MTHFR and T/T of the MDM2 genes, whereas individually these SNPs do not show significant relationship with the survival of patients after surgery.

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“…An Asian-Japanese study reported reduced overall survival of carriers of the MDM2 rs2279744 TT genotype as compared to carriers of the TG or GG genotypes (P=0.02) for patients with stage I lung adenocarcinoma (26). An Asian-Chinese study reported that carriers of MDM2 rs1690924 AG genotype were more sensitive to gastrointestinal toxicity than carriers of the wildtype homozygote GG [OR (95% CI) =2.32 (1.30-4.14), P=0.004)], suggesting MDM2 rs1690924 could be used to predict the toxicities of platinum-based chemotherapy in patients with advanced NSCLC (27).…”

Section: Discussionmentioning

confidence: 99%

“…Jar, data of TP53 from previous study (Yin et al submitted and revised); b , only list statistical significant models; C , balanced accuracy; d , cross-validation; e , P value based on 1,000 permutation test, statistical significant P value. 4784 chemotherapy outcome in lung cancer patients(26)(27)(28)(29).To the best of our knowledge, none of the remaining four htSNPs have been assessed previously in relation to lung cancer risk. The majority of the MDM2 SNP studies have…”

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confidence: 99%

Interaction between common variants of MDM2 and PPP1R13L and CD3EAP and TP53 SNPs in relation to lung cancer risk among Chinese

et al. 2020

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Background: Lung cancer is a complex disease that diagnosed the most common cancer and led cause of cancer death. MDM2 (MDM2 proto-oncogene) encodes a nuclear-localized E3 ubiquitin ligase. The encoded protein can promote tumor formation by targeting tumor suppressor proteins, such as TP53, for proteasomal degradation. Epidemiology studies have investigated the association of MDM2 single nucleotide polymorphisms (SNP) and interaction between genetic and environmental factors with lung cancer.Methods: This Chinese case-control study comprised 627 cases and 633 controls explored the role of MDM2 five htSNPs (rs1690924, rs1846402, rs2291857, rs3730581 and rs3730635, haplotype-tagging SNP) tagging 95% of the common haplotypes across the gene and the interactions of MDM2, PPP1R13L, CD3EAP and TP53 in the same pathological pathway on lung cancer risk, together with smoking-duration.Results: None of the htSNPs in MDM2 were associated with lung cancer risk in co-dominant, dominant, recessive, and log-additive models (adjusted for smoking-duration). Haplotype analysis showed that global haplotype association was statistically significant (P=0.0036, adjusted for smoking-duration) and haplotype5 (rs1690924 A -rs1846402 G -rs2291857 C -rs3730581 G -rs3730635 A ) was associated with reduced risk of lung cancer [OR (95%) =0.52 (0.33-0.82), P=0.0053, adjusted for smoking-duration]. MDR interaction analysis showed that two the best significant models and strong synergy between MDM2 and TP53.Conclusions: MDM2 five-htSNPs haplotype exhibited association with lung cancer susceptibility, interaction of MDM2 and TP53 htSNPs and smoking-duration contributed to lung cancer risk and strong synergy between MDM2 and TP53 htSNPs influenced lung cancer predisposition. Our results suggest that MDM2, TP53 and smoking-duration interact in relation to lung carcinogenesis.

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Prognostic potential of the MDM2 309T>G polymorphism in stage I lung adenocarcinoma

Cited by 6 publications

References 33 publications

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

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

Individual and combined effect ofTP53, MDM2, MDM4, MTHFR, CCR5,andCASP8gene polymorphisms in lung cancer

Interaction between common variants of MDM2 and PPP1R13L and CD3EAP and TP53 SNPs in relation to lung cancer risk among Chinese

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