Genetic variants ofGADD45A, GADD45BandMAPK14predict 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.

The P38α rs3804451 Variant Predicts Chemotherapy Response and Survival of Patients with Non–Small Cell Lung Cancer Treated with Platinum-Based Chemotherapy

“…The rs3804451 SNP is located on the 3′ untranslated region of MAPK14 ( P38a ) and likely to be functional as predicted by SNPInfo [22]. Indeed, in the present study, we showed that the high expression levels of P38a in tumor tissues were associated with the A allele.…”

“…Our previous study demonstrated that carriers of the MAPK14 rs3804451A variant allele had a significantly higher risk for grade 3/4 overall chemotherapy toxicity [22]; nevertheless, the effects of rs3804451GA/AA genotypes on PFS (Figure 3, C and D ) and OS (Figure 3, E and F ) between different toxicity subgroups showed no difference in the present study ( P  = .676 and .090, respectively) (Supplemental Table S8), suggesting that there was a direct effect of the A allele on PFS and OS, which was not mediated by the toxicity.…”

“…Because our previous study suggested that carriers of MAPK14 rs3804451GA/AA genotypes had a significantly higher risk for grade 3/4 overall chemotherapy toxicity [22], it is likely that the rs3804451A allele may reduce survival time by increasing chemotherapy toxicity. However, further homogeneity tests between subgroups with or without grade 3/4 overall chemotherapy toxicity did not appear to support any difference between these two subgroups.…”

“…Genomic DNA was extracted from blood samples of all the study subjects by using the DNA Blood Mini Kit (Qiagen, Valencia, CA). Preselected 11 independent, potentially functional SNPs of 9 key genes ( GADD45A, GADD45B, GADD45G, MAP2K7, MAP2K4, MAP3K4, MAPK8, MAPK9 , and MAPK14 ) [20], [21] involved in the JNK and P38α pathways were genotyped by using the TaqMan allelic discrimination assay on the ABI7900 HT sequence detector system (Applied Biosystems, Foster City, CA) [22]. More detailed information is provided in Supplemental Table S1.…”

Genetic variants of JNK and p38α pathways and risk of non‐small cell lung cancer in an Eastern Chinese population

“…Potentially functional SNPs of nine key genes ( i.e ., GADD45A, GADD45B, GADD45G, MAP2K7, MAP2K4, MAP3K4, MAPK8, MAPK9 and MAPK14 ) involved in the JNK and p38α pathways were selected according to the following criteria: ( i ) The minor allele frequency reported in HapMap was ≥5% in Chinese populations; ( ii ) in low linkage disequilibrium (LD) between SNPs by using an r 2 threshold of 0.8; ( iii ) at the two ends of these genes, such as 5′ UTRs, or 3′UTRs, which may be the regulatory regions of the genes; and ( iv ) potentially affect functions as predicted by SNPinfo (http://snpinfo.niehs.nih.gov/snpinfo/snpfunc.htm) such as transcription factor binding site (TFBS) and miRNA binding site activity; positive SNPs that have been previously reported to be associated with acute lung injury and inter‐ventricular septum hypertrophy are also included. As a result, only 11 SNPs could be selected and genotyped by the TaqMan real‐time PCR method with the Sequence Detection Software on an ABI‐Prism 7900 instrument according to the manufacturer's instructions (Applied Biosystems, Foster City, CA) as described previously . Their predicted functions and related information are summarized in Supporting Information Table S1, and those ungenotyped SNPs that are in linkage disequilibrium (LD) with these 11 SNPs are presented in Supporting Information Table S2.…”