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.
Highlights
Lung cancer is one of the most fatal human malignancies, the leading cause of cancer-related deaths in China [1]
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)
The characteristics and toxicity events in this patient population are summarized in Table 1 for both the discovery and validation groups, and all the patients had advanced NSCLC treated with platinum-based chemotherapy as the Patient characteristic All patients Discovery group
Summary
Lung cancer is one of the most fatal human malignancies, the leading cause of cancer-related deaths in China [1]. Platinum (cisplatin or carboplatin) double-agent chemotherapy is recommended as the first-line treatment for patients with advanced non–small cell lung cancer (NSCLC) without sensitive EGFR mutations according to the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN guidelines, http://www.nccn.org/professionals/). Platinum compounds www.impactjournals.com/oncotarget induce DNA damage, inhibit DNA replication, and activate a number of signal transduction pathways leading to cancer cell death [3]. These drugs damage normal cells, leading to severe adverse events [4, 5]. Some cancer patients treated with chemotherapies often need to decrease drug doses or stop treatment due to severe adverse events
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