Division of Thoracic and Visceral Organ Surgery, Gunma University Graduate School of Medicine, Maebashi, Japan
Kimihiro Shimizu , Yasuaki Enokida , Jun Atsumi , Seiichi Kakegawa , Yoshiaki Takase , Seshiru Nakazawa , Toshiteru Nagashima , Yoichi Ohtaki , Kazumi Tanaka , Kyoichi Kaira , Izumi Takeyoshi
Background: The MDM2 protein plays an important role in regulating cell proliferation and apoptosis by ubiquitination and proteosome-mediated degradation of p53. c.309 (rs2279744) polymorphism (T>G) in the MDM2 intronic promoter has been reported as a susceptibility and/or prognostic factor in various cancers. The purpose of this study was to investigate the risk factors for worse survival in patients with pathological (p-) stage I lung adenocarcinoma. Methods: We retrospectively reviewed 179 stage I lung adenocarcinoma patients. Clinicopathological and genetic characteristics including MDM2 SNP309, p53 codon72, as well as EGFR, KRAS, and p53 mutation were analyzed. Associations between these factors and survival outcome were analyzed by cox proportional hazards models. We further evaluated the associations of prognostic effects of SNP309 and smoking status or gene mutation status by stratified analyses. Results: A significant association was found between pleural invasion or lymphatic invasion and SNP309 TT genotype (TT vs. TG+GG, p= .027, p= .008, respectively; χ2 test) Overall-survival (OS) of patients with MDM2 TT genotype was significantly shorter than that with TG genotype and GG genotype (p= .048 and p= .009, respectively by log-rank test). A multivariate analysis of OS showed that MDM2 genotype (TT; Hazard Ratio [HR] =3.7, 95% confidential interval [CI] 1.5 to 9.2, p= .005) was an independently significant prognostic factor. Subgroup analysis also showed that TT genotype was especially associated with worse OS among smoker group (HR=6.75, 95%CI 1.90 to 24.0, p= .005), EGFR wild-type group (HR=3.75, 95%CI 1.22 to 11.6, p= .022), p53 wild-type group (HR=7.00, 95%CI 2.30 to 21.3, p= .001), and p53 codon72 RR+RPgroup (HR=5.44, 95%CI 1.91 to 15.5, p= .002). Conclusions: Our findings suggest that MDM2 TT genotype is associated with worse OS among p-stage I lung adenocarcinoma patients, particularly in the smoker group, EGFR wild-type group, p53 wild-type group, and p53 codon72 RR+RP group.
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