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Lung cancer is the first leading cause of cancer deaths. Chemotherapy toxicity is one of factors that limited the efficacy of platinum-based chemotherapy in lung cancer patients. Transporters and DNA repair genes play critical roles in occurrence of platinum-based chemotherapy toxicity. To investigate the relationships between transporter and DNA repair gene polymorphisms and platinum-based chemotherapy toxicity in lung cancer patients, we selected 60 polymorphisms in 14 transporters and DNA repair genes. The polymorphisms were genotyped in 317 lung cancer patients by Sequenom MassARRAY. Logistic regression was performed to estimate the association of toxicity outcome with the polymorphisms by PLINK. Our results showed that polymorphisms of SLC2A1 (rs3738514, rs4658, rs841844) were significantly related to overall toxicity. XRCC5 (rs1051685, rs6941) and AQP2 (10875989, rs3759125) polymorphisms were associated with hematologic toxicity. AQP2 polymorphisms (rs461872, rs7305534) were correlated with gastrointestinal toxicity. In conclusion, genotypes of these genes may be used to predict the platinum-based chemotherapy toxicity in lung cancer patients.

// Yu Zhang 1, 3 , Jing-Jing Yu 3 , Yan Tian 3 , Zheng-Zheng Li 3 , Cai-Yi Zhang 3 , Shu-Fen Zhang 3 , Lan-Qin Cao 3 , Yi Zhang 3 , Chen-Yue Qian 1, 2 , Wei Zhang 1, 2 , Hong-Hao Zhou 1, 2 , Ji-Ye Yin 1, 2 , Zhao-Qian Liu 1, 2 1 Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, P. R. China 2 Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, P. R. China 3 Department of Obstetrics & Gynecology, Xiangya Hospital, Central South University, Changsha 410008, P. R. China Correspondence to: Zhao-Qian Liu, e-mail: liuzhaoqian63@126.com Ji-Ye Yin, e-mail: yinjiye@csu.edu.cn Keywords: eIF3a, platinum, ovarian cancer, drug resistance, XPC Received: April 30, 2015 Accepted: June 29, 2015 Published: July 11, 2015 ABSTRACT The eukaryotic translation initiation factor 3a (eIF3a) is one of the core subunits of the translation initiation complex eIF3, responsible for ribosomal subunit joining and mRNA recruitment to the ribosome. Our previous study identified that it was correlated with platinum response in lung cancer. The current study aims to test the hypothesis that eIF3a may affect the drug response and prognosis of ovarian cancer patients receiving platinum-based chemotherapy by regulating xeroderma pigmentosum complementation group C (XPC) and p27 Kip1 . Immunohistochemistry and western blot was used to determine the expression of eIF3a in 126 human ovarian cancer tissues followed by association analysis of eIF3a expression with patient’s response and survival. Ectopic over-expression and RNA interference knockdown of eIF3a were carried out in A2780/cisplatin (DDP) and its parental A2780 cells, respectively, to determine the effect of altered eIF3a expression on cellular response to cisplatin by employing MTT assay. Western Blot analyses were also carried out to determine the regulation of eIF3a on XPC and p27 Kip1 . eIF3a expression was associated with response of ovarian cancer patients to DDP-based chemotherapy and their survival. Overexpression and knockdown of eIF3a increased and decreased the cellular response to cisplatin in A2780/DDP and A2780 cells, respectively. In addition, XPC and p27 Kip1 were down regulated by eIF3a. eIF3a improves ovarian cancer patients’ response to DDP-based chemotherapy via down regulating XPC and p27 Kip1 .

Eukaryotic translation initiation factor 3 subunit A (eIF3a) plays critical roles in regulating the initiation of protein translation, and eIF3a is highly expressed in lung cancer. In this study, we investigated the association of the positively selected SNPs of eIF3a with the response to and toxicity of platinum-based chemotherapy in Chinese patients with non-small cell lung cancer (NSCLC). SNP data for eIF3a locus were downloaded from HapMap database. For each SNP, haplotype, LD profile and population differentiation were analyzed. The long-range haplotype (LRH) test was employed to identify positively selected SNPs of eIF3a. A total of 325 NSCLC patients were enrolled and genotyped for these SNPs. Five positively selected (rs1409314, rs4752219, rs4752220, rs7091672 and rs10510050) and 5 non-positively selected SNPs (rs10886342, rs11198804, rs2275112, rs10787899 and rs4752269) were identified in the LRH test. However, none of them was correlated with the platinum-based chemotherapy response. In contrast, 4 of the positively selected SNPs (rs1409314, rs4752219, rs4752220 and rs7091672) were significantly correlated with the toxicities tested (neutropenia, anemia, thrombocytopenia, emesis and hepatotoxicity). In addition, rs10510050 was significantly correlated with thrombocytopenia, emesis and hepatotoxicity. None of the 5 non-positively selected SNPs was correlated with the 5 toxicities. The positively selected SNPs of eIF3a are significantly correlated with platinum-based chemotherapy toxicities in Chinese NSCLC patients.

To investigate the influence of ABCB1 polymorphisms on prognostic outcomes in Chinese patients with de novo intermediate-risk acute myeloid leukemia (AML) and to examine the gene expression level in relation to the genetic variation.In total, 263 Chinese intermediate-risk AML patients treated with anthracycline and cytarabine were enrolled. G2677T, C1236T, and C3435T of the ABCB1 gene were analyzed by the allele-specific matrix-assisted laser desorption. Expression of ABCB1 messenger RNA (mRNA) was tested in 101 patients of known genotype and haplotype for ABCB1 polymorphisms. Basic clinical characteristics of these patients were collected from medical records.Survival analysis showed that patients with AML (TTT haplotype) had a longer overall survival (OS) (p 0.001, 29.2 months, 95 % confidence interval [CI], 26.9-31.5 months) and relapse-free survival (RFS) (p = 0.005, 21.8 months, 95 % CI, 19.5-24.0 months) compared with those without TTT haplotype (21.9 months, 95 % CI, 19.6-24.2 months; 16.5 months, 95 % CI, 14.6-18.5 months). After adjusting for age; gender; leukocyte count; hemoglobin level; platelet levels; French, American, and British classification; lactate dehydrogenase levels; Eastern Cooperative Oncology Group performance status; nucleophosmin gene; and fms-related tyrosine kinase 3 gene, the multivariate survival analysis showed that the TTT haplotype appeared to be a predicting factor for OS (p = 0.001, hazard ratio = 1.854, 95 % CI, 1.301-2.641) and RFS (p = 0.009, hazard ratio = 1.755, 95 % CI, 1.153-2.671). Moreover, a significant association between the TTT haplotype and relapse in AML patients was observed in this study (p = 0.002, odds ratio = 0.410, 95 % CI, 0.235-0.715). Gene expression level was significantly lower in patients with the TTT haplotype than in the patients with the other haplotypes (p = 0.004).The findings suggested the TTT haplotype was possibly related to the OS, RFS, and relapse in Chinese patients with AML.

This study aims to investigate the influence of ATP7B genetic polymorphism to platinum-based chemotherapy in Chinese Han lung cancer patients. A total of 338 Chinese Han lung cancer patients were enrolled in this study. All patients underwent at least two cycles of platinum-based chemotherapy. Four tag SNPs of ATP7B (rs1061472, rs9535826, rs7999812, and rs9535828) were selected to evaluate their impacts to platinum-based chemotherapy in these patients. ATP7B rs9535828 and rs9535826 were found to be associated with platinum resistance in Chinese Han lung cancer patients. Patients with A allele in ATP7B rs9535828 presented an increased susceptibility to platinum drugs (OR 1.96, 95 % CI 1.17–3.30, p

Summary The aim of the present study was to investigate the association of genetic polymorphisms in high mobility group box 1 and 2 (HMGB1 and HMGB2, respectively) with platinum-based chemotherapy responses in Chinese lung cancer patients. In total, 338 Chinese lung cancer patients (154 responders and 184 non-responders) were recruited to the study. All patients received at least two cycles of first-line platinum-based chemotherapy. Three tagging single nucleotide polymorphisms (SNPs) of HMGB1 and two tagging SNPs of HMGB2 were detected in patients. We found that rs1412125 and rs2249825 of HMGB1 were significantly associated with the platinum-based chemotherapy response in both recessive and genotypic models. In addition, rs1412125 showed significant association with platinum-based chemotherapy response for the subgroup of patients aged >55 years in additive, recessive and genotypic models. No significant associations were detected between other SNPs and the platinum-based chemotherapy response. The HMGB1 SNPs (rs1412125 and rs2249825) were associated with platinum-based chemotherapy responses in Chinese lung cancer patients. In conclusion, HMGB1 SNPs may serve as potential biomarkers for predicting the efficacy of platinum-based chemotherapy.

Lung cancer is the leading cause of cancer deaths in the world. The toxicity of platinum-based chemotherapy is a main reason limiting its clinical effects. RAC1, as a member of the Rho family of small guanosine triphosphatases (GTPases), was reported to be related to most cancers, such as breast cancer, gastric cancer, testicular germ cell cancer, and lung cancer. Its potential of becoming a drug target in cancer treatment has been investigated in recent years. The aim of this study was to investigate the association between genetic polymorphisms and platinum-based chemotherapy toxicity. We enrolled 317 lung cancer patients randomly. Nineteen polymorphisms of HSP genes and Rho family genes were genotyped by Sequenom MassARRAY. The logistic regression was performed by PLINK to compare the relevance of polymorphisms and toxicity outcome. We found that the polymorphisms of RAC1 rs836554, rs4720672, and rs12536544 were significantly associated with platinum-based chemotherapy toxicity (p = 0.018, p = 0.044, and p = 0.021, respectively). RAC1 rs836554, rs4720672, and rs12536544 polymorphisms may be novel and useful genetic markers to predict the toxicity induced by platinum-based chemotherapy in lung cancer patients.

In this study, we aimed to explore the long noncoding RNA expression pattern in squamous cell lung cancer (SQCC) on a genome-wide scale. Total RNAs were extracted from 16 lung SQCC patients’ normal and matched lung cancer tissues by Trizol reagent. The expression level of genome-wide scale lncRNA and mRNA was determined by microarray. qRT-PCR was used to validate the lncRNA expression level in 47 patients. Data analyses were performed using R and Bioconductor. A total of 2,748 up and 852 down regulated probes were identified to be significantly and differentially expressed in tumor tissues. The annotation result of their co-expressed mRNAs showed that the most significantly related category of GO analysis was development and differentiation, while the most significantly related pathway was cell cycle. Subgroup analysis identified that 46 and 18 probes were specifically differentially expressed in smoking and moderately differentiated tumors, respectively. Our study indicated that clusters of lncRNAs were significantly and differentially expressed in SQCC compared with normal tissues in the same subject. They may exert a significant role in lung cancer development and could be potential targets for future treatment of SQCC.

Platinum-based therapy is commonly used for the treatment of lung cancer and has been widely accepted by clinicians, but the chemotherapy responses differ greatly among individuals. TNF/TNF-R1/R2 signal pathway can trigger the extrinsic pathway of apoptosis after DNA damage was caused by platinum-based treatment. The aim of this study was to investigate the association of TNF -308 A/G, TNF-R1 -383A>C, -609T>G and TNF-R2 +676 T>G and the response of platinum-based chemotherapy in 313 Chinese advanced-stage non-small-cell lung cancer (NSCLC) patients. MassARRAY was used to detect these four SNPs in three apoptosis-related genes. TNF -308 A/G was significantly correlated with better clinical benefit. Patients carrying A allele tended to have a favorable prognosis after treated with platinum-based chemotherapy (P=0.043, OR=0.488, 95%CI=0.244-0.979). The patients with CA genotype have significantly reduced risk of platinum resistance compared with wild-type homozygotes CC genotype (P=0.025, OR=0.447, 95% CI=0.220-0.906). No association was found in other polymorphisms. In conclusion, our data suggest that TNF-308 A/G polymorphism may serve as the indicator of platinum-based chemotherapy response in NSCLC patients.

Platinum-based chemotherapy toxicity is always one of the serious problems from which lung cancer patients suffer. The genetic polymorphism of WISP1 was revealed to be associated with susceptibility and platinum-based chemotherapy response in our previous studies. In this study, we aimed to investigate the relationship of WISP1 genetic polymorphisms with platinum-based chemotherapy toxicity in lung cancer patients. A total of 412 lung cancer patients were enrolled in this study, and 28 polymorphisms of the WISP1 gene were genotyped by SequenomMassARRAY. We found that WISP1 polymorphisms (rs2929965, rs2929969, rs2929970, rs2929973 and rs754958) were related to the overall chemotherapy toxicity of lung cancer in subgroup analyses. Rs16904853, rs2929970, rs2977549 and rs2977551 (p = 0.021, 0.028, 0.024, 0.048, respectively) polymorphisms were significantly associated with hematologic toxicity. Rs2929946, rs2929970, rs2977519, rs2977536, rs3739262 and rs754958 (p = 0.031, 0.046, 0.029, 0.016, 0.042, 0.035, respectively) polymorphisms were significantly associated with the gastrointestinal toxicity of lung cancer. Genotypes of WISP1 may be novel and useful biomarkers for predicting platinum-based chemotherapy toxicity in lung cancer patients.

Lung cancer is one of the most common cancers and is the leading cause of death worldwide. Platinum-based chemotherapy is the main treatment method in lung cancer patients. Our previous studies indicated that single nucleotide polymorphisms (SNPs) in some transporter genes played important role in platinum-based chemotherapy efficacy. The aim of this study was to investigate the association of SNPs in transporter genes and platinum-based chemotherapy efficacy. The main polymorphisms on transporters OCT2, LRP, AQP2, AQP9 and TMEM205 genes were genotyped in 338 lung cancer patients. The rs195854 in genotypic model, rs896412 in genotypic and recessive models for all subjects showed significant association with chemotherapy response. In stratification analysis, TMEM205 rs896412, OCT2 rs1869641 and rs195854, AQP9 rs1516400 and AQP2 rs7314734 showed significant relation to chemotherapy response. In conclusion, the genetic polymorphisms in OCT2, AQP2, AQP9 and TMEM205 may contribute to chemotherapy response in lung cancer patients.

Background Platinum-based chemotherapy is the main treatment method for lung cancer patients. The genetic polymorphisms of Wnt-inducible signaling pathway protein 1 ( WISP1 ) were reported to be associated with the development of diverse lung diseases. In this study, we aimed to investigate the relationship of WISP1 genetic polymorphisms with lung cancer susceptibility and platinum-based chemotherapy response in Chinese lung cancer patients. Materials and Methods A total of 556 lung cancer patients and 254 healthy controls were enrolled onto this study. The 28 polymorphisms of the WISP1 gene were genotyped by the Sequenom MassARRAY system. Results We found that WISP1 rs16893344, rs2977530, rs2977537, and rs62514004 ( P = .009, .033, .049, and .036, respectively) polymorphisms were related to susceptibility of lung cancer; and WISP1 rs11778573 ( P = .023, nonsmokers), rs16893344 ( P = .013, ≥ 50 years old), rs2977536 ( P = .039, ≥ 50 years old; P = .044, nonsmokers; P = .047, non–small-cell lung cancer, respectively), rs2977549 ( P = .013, smokers), and rs62514004 ( P = .033, ≥ 50 years old) polymorphisms were significantly associated with platinum-based chemotherapy response in lung cancer patients. Conclusion Genotypes of WISP1 may be novel and useful biomarkers for diagnosis of lung cancer and evaluation of platinum-based chemotherapy response in lung cancer patients.