title: Genetic variants of GADD45A, GADD45B and MAPK14 predict platinum-based chemotherapy-induced toxicities in Chinese patients with non-small cell lung cancer.
abstract: The JNK and P38α pathways play a crucial role in tissue homeostasis, apoptosis and autophagy under genotoxic stresses, but it is unclear whether single nucleotide polymorphisms (SNPs) of genes in these pathways play a role in platinum-based chemotherapy-induced toxicities in patients with advanced non-small cell lung cancer (NSCLC). We genotyped 11 selected, independent, potentially functional SNPs of nine genes in the JNK and P38α pathways in 689 patients with advanced NSCLC treated with platinum-combination chemotherapy regimens. Associations between these SNPs and chemotherapy toxicities were tested in a discovery group of 345 patients and then validated in a replication group of 344 patients. In both discovery and validation groups as well as their pooled analysis, carriers of GADD45B rs2024144T variant allele had a significantly higher risk for severe hematologic toxicity and carriers of MAPK14 rs3804451A variant allele had a significantly higher risk for both overall toxicity and gastrointestinal toxicity. In addition, carriers of GADD45A rs581000C had a lower risk of anemia, while carriers of GADD45B rs2024144T had a significantly higher risk for leukocytopenia or agranulocytosis. The present study provides evidence that genetic variants in genes involved in the JNK and P38α pathways may predict platinum-based chemotherapy toxicity outcomes in patients with advanced NSCLC. Larger studies of other patient populations are needed to validate our findings.
authors.affiliation: Cancer Institute, Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Jia
authors.affiliation: Department of Oncology, Xinhua Hospital Affiliated to Shanghai Jiaotong University, School of Medicine, Shanghai, 200092, China.
authors.forename: Meiling
authors.initials: M
authors.lastname: Zhu
authors.affiliation: Cancer Institute, Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
authors.forename: Mengyun
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
authors.forename: Menghong
authors.initials: M
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences and Fudan Taizhou Institute of Health Sciences, Fudan University, Shanghai, 200032, China.
authors.forename: Ji
authors.initials: J
authors.lastname: Qian
authors.affiliation: Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Ding
authors.affiliation: Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Chang
authors.affiliation: Cancer Institute, Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.|Department of Medicine, Duke Cancer Institute, Duke University Medical Center, Duke University School of Medicine, Durham, North Carolina, 27710, USA.
authors.forename: Qingyi
authors.initials: Q
authors.lastname: Wei
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000943:Antigens, Differentiation / Q000235:genetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D044466:Asian People / Q000235:genetics; D016190:Carboplatin / Q000009:adverse effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics*; D002945:Cisplatin / Q000009:adverse effects; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D048308:Mitogen-Activated Protein Kinase 14 / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult; D000097642:GADD45 Proteins
chemical_list: D000943:Antigens, Differentiation; D016190:Carboplatin; D018797:Cell Cycle Proteins; D002945:Cisplatin; D048308:Mitogen-Activated Protein Kinase 14; D009687:Nuclear Proteins; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C086470:GADD45B protein, human
keywords: JNK and P3α pathways; adverse events; genetic variants; lung cancer; platinum-based chemotherapy