Genetic variants of GADD45A, GADD45B and MAPK14 predict platinum-based chemotherapy-induced toxicities in Chinese patients with non-small cell lung cancer

// Ming Jia 1, 2 , Meiling Zhu 3 , Mengyun Wang 1, 2 , Menghong Sun 4 , Ji Qian 5 , Fei Ding 4 , Jianhua Chang 6 , Qingyi Wei 1, 2, 7 1 Cancer Institute, Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Shanghai, 200032, China 2 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China 3 Department of Oncology, Xinhua Hospital Affiliated to Shanghai Jiaotong University, School of Medicine, Shanghai, 200092, China 4 Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China 5 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 6 Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China 7 Department of Medicine, Duke University School of Medicine and Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina, 27710, USA Correspondence to: Jianhua Chang, e-mail: changjianhua@163.com Qingyi Wei, e-mail: weiqingyi@yahoo.com , qingyi.wei@duke.edu Keywords: JNK and P3α pathways, genetic variants, lung cancer, platinum-based chemotherapy, adverse events Received: December 07, 2015     Accepted: February 29, 2016     Published: March 14, 2016 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.