Abstract
BackgroundTaxane is one of the first line treatments of lung cancer. In order to identify novel single nucleotide polymorphisms (SNPs) that might contribute to taxane response, we performed a genome-wide association study (GWAS) for two taxanes, paclitaxel and docetaxel, using 276 lymphoblastoid cell lines (LCLs), followed by genotyping of top candidate SNPs in 874 lung cancer patient samples treated with paclitaxel.MethodsGWAS was performed using 1.3 million SNPs and taxane cytotoxicity IC50 values for 276 LCLs. The association of selected SNPs with overall survival in 76 small or 798 non-small cell lung cancer (SCLC, NSCLC) patients were analyzed by Cox regression model, followed by integrated SNP-microRNA-expression association analysis in LCLs and siRNA screening of candidate genes in SCLC (H196) and NSCLC (A549) cell lines.Results147 and 180 SNPs were associated with paclitaxel or docetaxel IC50s with p-values <10-4 in the LCLs, respectively. Genotyping of 153 candidate SNPs in 874 lung cancer patient samples identified 8 SNPs (p-value < 0.05) associated with either SCLC or NSCLC patient overall survival. Knockdown of PIP4K2A, CCT5, CMBL, EXO1, KMO and OPN3, genes within 200 kb up-/downstream of the 3 SNPs that were associated with SCLC overall survival (rs1778335, rs2662411 and rs7519667), significantly desensitized H196 to paclitaxel. SNPs rs2662411 and rs1778335 were associated with mRNA expression of CMBL or PIP4K2A through microRNA (miRNA) hsa-miR-584 or hsa-miR-1468.ConclusionsGWAS in an LCL model system, joined with clinical translational and functional studies, might help us identify genetic variations associated with overall survival of lung cancer patients treated paclitaxel.
Highlights
Taxane is one of the first line treatments of lung cancer
Single nucleotide polymorphisms (SNPs) for AA were imputed using both CEU (Utah residents with Northern and Western European ancestry from the Centre d’Etude du Polymorphisme Humain (CEPH) collection) and YRI (Yoruba in Ibadan, Nigeria) data, SNPs for CA were imputed based on CEU data, and SNPs for Han Chinese-American (HCA) were imputed based on the CHB (Han Chinese in Beijing, China) and JPT (Japanese in Tokyo, Japan) data
In order to understand biological mechanisms underlying the variation in response to taxane and to identify novel biomarkers which might be helpful for individualized taxane chemotherapy, we performed pharmacogenomic studies of paclitaxel and docetaxel in 276 lymphoblastoid cell lines (LCLs), followed by association studies of candidate SNPs identified during the analysis in LCLs using DNA samples from non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) patients treated with paclitaxel
Summary
In order to identify novel single nucleotide polymorphisms (SNPs) that might contribute to taxane response, we performed a genome-wide association study (GWAS) for two taxanes, paclitaxel and docetaxel, using 276 lymphoblastoid cell lines (LCLs), followed by genotyping of top candidate SNPs in 874 lung cancer patient samples treated with paclitaxel. A clinical GWAS with 1040 patients treated with paclitaxel identified 3 SNPs located in the EPHA5, FGD4 and NDRG1 genes that were associated with peripheral neuropathy [18]. All of these results suggest that genetic variation plays an important role in interindividual variation in taxane response
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