Association Of Endoplasmic Reticulum Stress Pathway - Associated Gene Polymorphism With Platinum - Containing Chemotherapy In Advanced Non - Small Cell Lung Cancer

The platinum combination chemotherapy is the most major therapy for the advanced non-small cell lung cancer (NSCLC) patients. But the outcome and toxicity are variable between individuals, in which the single nucleotide polymorphisms play a key role. The endoplasmic reticulum stress (ERS) has a crucial position in maintaining cellular homeostasis, but on the other hand can also induce cell death when severe stress continues. In this study, we investigated the association of39SNPs from8genes (HSPA5, HSP90B1, XBP1, VCP, CALCR, CANX, MAPK3, EIF2S1) relating ERS with the response and toxicity during platinum combination chemotherapy in advanced NSCLC patients. We proposed to find significant SNPs as predictive markers that could direct individualized therapy to minimize toxicity and promote response in platinum-based chemotherapy.Our investigation revealed that, VCP rs2074549variant homozygote CC compared with its wild-type homozygote, in the subgroup of patients receiving cisplatin plus Navelbine treatment, showed significant association with the increased risk of leukocytopenia toxicity (adjusted OR=7.690,95%CI=2.802-21.110, P=7.490E-05], as well as the increased risk of agranulocytosis toxicity (adjusted OR=11.960,95%CI=3.877-36.920, P=1.851E-05), and rs2074549variant homozygote also significantly increased the risk of leukocytopenia toxicity in elder patients (>58years old).The genotype GCT in the haplotype block, whick was constitutive of rs1053318, rs2074549, and rs514492, showed significant association with the increased risk of leukocytopenia toxicity in the subgroup of patients receiving cisplatin plus Navelbine treatment (adjusted OR=2.949,95%CI=1.622-5.363, P=3.943E-04).XBP1rs2269577variant homozygote GG compared with its wild-type homozygote showed significant increased risk of gastrointestinal toxicity in the subgroup of adenocarcinoma (adjusted OR=4.103,95%CI=1.894-8.885, P=3.432E-04).In addition, numbers of SNPs of other genes also showed significant association with response or toxicity in platinum-treated NSCLC.To explore the functional role of XBP1and rs2269577in the gastrointestinal outcome, we detected the variation of XBP1mRNA levels in HEK293cell line and GES-1cell line treated with cisplatin as first step. The XBP1-U mRNA and XBP1-S mRNA both decreased significantly in GES-1treated with ciaplatin, which were opposite in HEK293. Next we cloned the promoter region of XBP1containing rs2269577into pGL3-Basic vector to construct recombinants of distinct alleles of rs2269577, as XBP1-pGL3-Basic-C and XBP1-pGL3-Basic-G. Dual-luciferase assay was detected after recombinants were transfected into HEK293and GES-1respectively, and XBP1-pGL3-Basic-G decreased luciferase-reporter expression levels significantly both in HEK293and GES-1. Thus we concluded that the reduced XBP1mRNA levels in gastrointestinal cells suffered with platinum agents and the decreased transcriptional efficiency of XBP1promoter caused by rs2269577C>G contributed together to the significant association between rs2269577and gastrointestinal toxicity in platin-treated NSCLC.