Ji Qian1, Hongliang Liu2, Shaohua Gu3, Qihan Wu4, Xueying Zhao3, Wenting Wu5, Haijian Wang3, Jiucun Wang3, Hongyan Chen3, Wei Zhang6, Qingyi Wei7, Li Jin3, Daru Lu8. 1. Cancer Institute, Fudan University Shanghai Cancer Center, and Department of Oncology, Fudan University Shanghai Medical College, Shanghai, China; State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, Fudan University School of Life Sciences and Fudan Taizhou Institute of Health Sciences, Shanghai, China. Electronic address: jiqian@fudan.edu.cn. 2. Duke Cancer Institute, Duke University Medical Center, Durham, NC. 3. State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, Fudan University School of Life Sciences and Fudan Taizhou Institute of Health Sciences, Shanghai, China. 4. East China Normal University School of Life Science, Shanghai, China. 5. State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, Fudan University School of Life Sciences and Fudan Taizhou Institute of Health Sciences, Shanghai, China; Beyster Center for Genomics of Psychiatric Diseases, Department of Psychiatry, University of California, San Diego, La Jolla, CA. 6. Department of Respiratory Disease, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, China. 7. Cancer Institute, Fudan University Shanghai Cancer Center, and Department of Oncology, Fudan University Shanghai Medical College, Shanghai, China; Duke Cancer Institute, Duke University Medical Center, Durham, NC. 8. State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, Fudan University School of Life Sciences and Fudan Taizhou Institute of Health Sciences, Shanghai, China. Electronic address: darulu@hotmail.com.
Abstract
INTRODUCTION: Platinum agents can cause the formation of DNA adducts and induce apoptosis to eliminate tumor cells. The aim of the present study was to investigate the influence of genetic variants of MDM2 on chemotherapy-related toxicities and clinical outcomes in patients with advanced non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: We recruited 663 patients with advanced NSCLC who had been treated with first-line platinum-based chemotherapy. Five tagging single nucleotide polymorphisms (SNPs) in MDM2 were genotyped in these patients. The associations of these SNPs with clinical toxicities and outcomes were evaluated using logistic regression and Cox regression analyses. RESULTS: Two SNPs (rs1470383 and rs1690924) showed significant associations with chemotherapy-related toxicities (ie, overall, hematologic, and gastrointestinal toxicity). Compared with the wild genotype AA carriers, patients with the GG genotype of rs1470383 had an increased risk of overall toxicity (odds ratio [OR], 3.28; 95% confidence interval [CI], 1.34-8.02; P = .009) and hematologic toxicity (OR, 4.10; 95% CI, 1.73-9.71; P = .001). Likewise, patients with the AG genotype of rs1690924 showed more sensitivity to gastrointestinal toxicity than did those with the wild-type homozygote GG (OR, 2.32; 95% CI, 1.30-4.14; P = .004). Stratified survival analysis revealed significant associations between rs1470383 genotypes and overall survival in patients without overall or hematologic toxicity (P = .007 and P = .0009, respectively). CONCLUSION: The results of our study suggest that SNPs in MDM2 might be used to predict the toxicities of platinum-based chemotherapy and overall survival in patients with advanced NSCLC. Additional validations of the association are warranted.
INTRODUCTION:Platinum agents can cause the formation of DNA adducts and induce apoptosis to eliminate tumor cells. The aim of the present study was to investigate the influence of genetic variants of MDM2 on chemotherapy-related toxicities and clinical outcomes in patients with advanced non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: We recruited 663 patients with advanced NSCLC who had been treated with first-line platinum-based chemotherapy. Five tagging single nucleotide polymorphisms (SNPs) in MDM2 were genotyped in these patients. The associations of these SNPs with clinical toxicities and outcomes were evaluated using logistic regression and Cox regression analyses. RESULTS: Two SNPs (rs1470383 and rs1690924) showed significant associations with chemotherapy-related toxicities (ie, overall, hematologic, and gastrointestinal toxicity). Compared with the wild genotype AA carriers, patients with the GG genotype of rs1470383 had an increased risk of overall toxicity (odds ratio [OR], 3.28; 95% confidence interval [CI], 1.34-8.02; P = .009) and hematologic toxicity (OR, 4.10; 95% CI, 1.73-9.71; P = .001). Likewise, patients with the AG genotype of rs1690924 showed more sensitivity to gastrointestinal toxicity than did those with the wild-type homozygote GG (OR, 2.32; 95% CI, 1.30-4.14; P = .004). Stratified survival analysis revealed significant associations between rs1470383 genotypes and overall survival in patients without overall or hematologic toxicity (P = .007 and P = .0009, respectively). CONCLUSION: The results of our study suggest that SNPs in MDM2 might be used to predict the toxicities of platinum-based chemotherapy and overall survival in patients with advanced NSCLC. Additional validations of the association are warranted.