title: Polymorphisms of p53 and MDM2 genes are associated with severe toxicities in patients with non-small cell lung cancer.
abstract: Adverse events in platinum-based chemotherapy for patients with advanced non-small cell lung cancer (NSCLC) are major challenges. In this study, we investigated the role of the p53 and MDM2 genes in predicting adverse events in NSCLC patients treated with platinum-based chemotherapy. Specifically, we examined the p53 p. Pro72Arg (rs1042522), MDM2 c.14 + 309T>G (rs2279744) and MDM2 c.- 461C > G (rs937282) polymorphisms using PCR-based restriction fragment length polymorphism (RFLP) in 444 NSCLC patients. We determine that MDM2 c.14 + 309T > G was significantly associated with severe hematologic and overall toxicities for advanced NSCLC patients treated with platinum-based chemotherapy, especially for patients aged 57 and younger. This was also true for patients with adenocarcinoma. Second, we determine that severe gastrointestinal toxicities in patients with heterozygous MDM2 c.-461C > G were significantly higher than in patients with the G/G genotype. Third, patients with the MDM2 c.-461C > G - c.14 + 309T > G CT haplotype show much higher toxicities than those of CG haplotype. Moreover, patients carrying the MDM2 c.-461 > G -c.14 + 309T > G CG/CT diplotype exhibited higher toxicities than those carrying CG/CG. Fourth, we found that the p53 p. Pro72Arg polymorphism interacts with both age and genotype. In addition, no significant associations were observed between the 3 SNPs and the response to first-line platinum-based chemotherapy in advanced NSCLC patients. In summary, we found that the p53 p. Pro72Arg, MDM2 c.14 + 309T > G and MDM2 c.-461C > G polymorphisms are associated with toxicity risks following platinum-based chemotherapy treatment in advanced NSCLC patients. We suggest that MDM2 c.14 + 309T > G may be used as a candidate biomarker to predict adverse events in advanced NSCLC patients who had platinum-based chemotherapy treatment.
authors.affiliation: a Department of Biological Science and Technology and State Key Laboratory of Pharmaceutical Biotechnology; School of Life Sciences ; Nanjing University ; Nanjing , China.
authors.forename: Datong
authors.initials: D
authors.lastname: Zheng
authors.forename: Yanping
authors.initials: Y
authors.lastname: Chen
authors.forename: Caijie
authors.initials: C
authors.lastname: Gao
authors.forename: Yongyue
authors.initials: Y
authors.lastname: Wei
authors.forename: Guochun
authors.initials: G
authors.lastname: Cao
authors.forename: Nan
authors.initials: N
authors.lastname: Lu
authors.forename: Yayi
authors.initials: Y
authors.lastname: Hou
authors.forename: Xiuqin
authors.initials: X
authors.lastname: Jiang
authors.forename: Jianjun
authors.initials: J
authors.lastname: Wang
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D064420:Drug-Related Side Effects and Adverse Reactions / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics*; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2
keywords: CBR, clinical benefit rate; CR, complete response; MDM2; NSCLC, non-small cell lung cancer; ORR, objective response rate; PCR-RFLP, PCR-based restriction fragment length polymorphism; PD, progressive disease; PR, partial response; PS, performance status; SCLC, small-cell lung cancer; SD, stable disease; SNP, single nucleotide polymorphism; TNM, tumor/node/metastasis; non-small cell lung cancer; p53; polymorphism; toxicity