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ABSTRACT: PURPOSE: Platinum-based chemotherapy is the most common treatment for patients with advanced non-small cell lung cancer (NSCLC). Genetic polymorphisms in the base excision repair (BER) pathway are suspected to influence the response of patients to this type of therapy. In this study, we investigated whether nonsynonymous single nucleotide polymorphisms (SNPs) in the BER pathway were associated with the response, progression-free survival (PFS) and overall survival (OS) of NSCLC patients following platinum-based chemotherapy. METHODS: We used TaqMan to genotype four SNPs (APE1 Asp148Glu, PARP1 Va1762Ala, XRCC1 Arg194Trp and XRCC1 Arg399Gln) in 147 patients with advanced NSCLC who had undergone routine platinum-based chemotherapy. RESULTS: Logistic regression analysis showed that subjects with the XRCC1-399 A allele had a significantly better response to platinum-based chemotherapy than those with the XRCC1-399 GG genotype (AA/AG vs. GG: adjusted OR = 2.35, 95 % CI = 1.11-5.00). Furthermore, multivariate Cox proportional hazard regression analysis showed that the PARP1-762 CC genotype was a significantly unfavorable prognostic factor for PFS (CC vs. CT/TT: adjusted HR = 1.90, 95 % CI = 1.02-3.52). In contrast, the APE1-148 GG genotype was a significantly protective prognostic factor for OS (GG vs. TT: adjusted HR = 0.33, 95 % CI = 0.12-0.92). CONCLUSIONS: We found that XRCC1 Arg399Gln, PARP1 Va1762Ala and APE1 Asp148Glu SNPs in the BER pathway may influence the prognosis of advanced NSCLC patients following platinum-based chemotherapy.
Cancer Chemotherapy and Pharmacology 03/2013; · 2.83 Impact Factor
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Ruyang Zhang,
Yang Zhao,
Minjie Chu,
Chen Wu,
Guangfu Jin,
Juncheng Dai,
Cheng Wang, Lingmin Hu,
Jianwei Gou,
Chen Qian,
Jianling Bai,
Tangchun Wu,
Zhibin Hu,
Dongxin Lin,
Hongbing Shen,
Feng Chen
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ABSTRACT: Genome-wide association studies (GWAS) have identified a number of genetic variants associated with lung cancer risk. However, these loci explain only a small fraction of lung cancer hereditability and other variants with weak effect may be lost in the GWAS approach due to the stringent significance level after multiple comparison correction. In this study, in order to identify important pathways involving the lung carcinogenesis, we performed a two-stage pathway analysis in GWAS of lung cancer in Han Chinese using gene set enrichment analysis (GSEA) method. Predefined pathways by BioCarta and KEGG databases were systematically evaluated on Nanjing study (Discovery stage: 1,473 cases and 1,962 controls) and the suggestive pathways were further to be validated in Beijing study (Replication stage: 858 cases and 1,115 controls). We found that four pathways (achPathway, metPathway, At1rPathway and rac1Pathway) were consistently significant in both studies and the values for combined dataset were 0.012, 0.010, 0.022 and 0.005 respectively. These results were stable after sensitivity analysis based on gene definition and gene overlaps between pathways. These findings may provide new insights into the etiology of lung cancer.
PLoS ONE 01/2013; 8(3):e57763. · 4.09 Impact Factor
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Guangfu Jin,
Hongxia Ma,
Chen Wu,
Juncheng Dai,
Ruyang Zhang,
Yongyong Shi,
Jiachun Lu,
Xiaoping Miao,
Meilin Wang,
Yifeng Zhou, [......],
Wen Tan,
Baosen Zhou,
Daru Lu,
Tangchun Wu,
Zhengdong Zhang,
Feng Chen,
Xinru Wang,
Zhibin Hu,
Dongxin Lin,
Hongbing Shen
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ABSTRACT: Cancer susceptibility loci identified in reported genome-wide association studies (GWAS) are often tumor-specific; however, evidence of pleiotropy of some genes/loci has also been observed and biologically plausible. We hypothesized that there are important regions in the genome harboring genetic variants associated with risk of multiple types of cancer. In the current study, we attempted to map genetic variants that have consistent effects on risk of multiple cancers using our existing genome-wide scan data of lung cancer, noncardia gastric cancer, and esophageal squamous-cell carcinoma with overall 5,368 cases and 4,006 controls (GWAS stage), followed by a further evaluation in additional 9,001 cases with one of these cancer types and 11,436 controls (replication stage). Five variants satisfying the criteria of pleiotropy with p values from 1.10 × 10(-8) to 8.96 × 10(-6) for genome-wide scans of three cancer types were further evaluated in the replication stage. We found consistent associations of rs2494938 at 6p21.1 and rs2285947 at 7p15.3 with these three cancers in both GWAS and replication stages. In combined samples of GWAS and replication stages, the minor alleles of rs2494938 and rs2285947 were significantly associated with an increased risk of the cancers (odds ratio [OR] = 1.15, 95% confidence interval [CI], 1.10-1.19 and OR = 1.17, 95% CI, 1.12-1.21), with the p values being 1.20 × 10(-12) and 1.26 × 10(-16), respectively, which are at a genome-wide significance level. Our findings highlight the potential importance of variants at 6p21.1 and 7p15.3 in the susceptibility to multiple cancers.
The American Journal of Human Genetics 10/2012; · 10.60 Impact Factor
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ABSTRACT: Recently, it has been shown that ectopic expression of several germ line genes, such as piwi, vasa, nos and aub, drives the growth of malignant brain tumors in Drosophila. A genome-wide association study (GWAS) of ∼18 000 subjects indicated that genetic variation at 22q12.2, the location of the conserved meiotic gene HORMAD2, may contribute to the risk of lung cancer in Han Chinese individuals. The expression pattern of human HORMAD2 in multiple human tissues was determined by RT-PCR. HORMAD2 protein expression and localization were analyzed in the human testis using immunohistochemistry. The expression of HORMAD2 in lung cancer and normal tissues was studied using quantitative RT-PCR and immunohistochemistry. HORMAD2 is predominantly expressed in human testis and weakly expressed in liver. HORMAD2 is ectopically expressed in nearly 10% of lung cancer samples from Chinese Han individuals. In conclusion, HORMAD2 is a novel cancer/testis gene discovered by GWAS, which may provide a new target for lung cancer research.
Molecular Human Reproduction 08/2012; · 3.85 Impact Factor
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ABSTRACT: Single-nucleotide polymorphisms (SNPs) of TERT rs2736098, rs2736100, and CLPTM1L rs402710 at 5p15.33 are significantly associated with risk of a spectrum of cancers. However, cervical cancer has been rarely evaluated. In this study, we genotyped the three SNPs in a case-control study with 1,033 cervical cancer cases and 1,053 cancer-free controls in a Chinese population. Logistic regression analyses showed that the two TERT SNPs both significantly associated with cervical cancer risk in the recessive model (rs2736098, AA vs. AG/GG: adjusted OR = 1.35, 95% CI = 1.06-1.72; rs2736100, CC vs. AC/AA: adjusted OR = 1.38, 95% CI = 1.11-1.73). However, no association was found between CLPTM1L rs402710 and cervical cancer. These results suggest that genetic variants in 5p15.33, especially in TERT, may be markers for susceptibility to cervical cancer. © 2012 Wiley Periodicals, Inc.
Molecular Carcinogenesis 01/2012; 51 Suppl 1:E118-22. · 3.16 Impact Factor
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Huan Guo,
Qifei Deng,
Chen Wu, Lingmin Hu,
Sheng Wei,
Ping Xu,
Dan Kuang,
Li Liu,
Zhibin Hu,
Xiaoping Miao,
Hongbing Shen,
Dongxin Lin,
Tangchun Wu
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ABSTRACT: The heat shock protein Hsp70 is crucial for regulating cellular homeostasis in stressed cells. Although the tumorigenic potential and prognostic applications of Hsp70 have been widely investigated, it remains unclear whether genetic variations of the human isoforms HSPA1L, HSPA1A, and HSPA1B are associated with cancer risk and prognosis. In this study, we genotyped six tagSNPs in these genes in 1,152 paired patients with lung cancer and controls, and then validated the results in additional cohorts of 1,781 patients with lung cancer and 1,038 controls. In addition, we evaluated the associations of these tagSNPs with survival in 330 patients with advanced non-small cell lung cancer (NSCLC) with additional validation in another 331 patients with advanced NSCLC. Functions of the risk variants identified were investigated using cell-based reporter assays. We found that the HSPA1B rs6457452T allele was associated with increased lung cancer risk compared with the rs6457452C allele in both data sets and also pooled analysis (adjusted OR = 1.41; P = 2.8 × 10(-5)). The HSPA1B rs2763979TT genotype conferred poor survival outcomes for patients with advanced NSCLC in two independent cohorts and pooled analysis [adjusted hazard ratio (HR) = 1.80, 1.61, and 1.66; P = 0.013, 0.036, and 0.002, respectively]. Lastly, we also found that the rs2763979T and rs6457452T alleles were each sufficient to reduce expression of transcriptional reporter constructs, when compared with the rs2763979C and rs6457452C alleles, respectively. Taken together, our findings define that functional HSPA1B variants are associated with lung cancer risk and survival. These Hsp70 genetic variants may offer useful biomarkers to predict lung cancer risk and prognosis.
Cancer Research 12/2011; 71(24):7576-86. · 7.86 Impact Factor
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Yongyong Shi,
Zhibin Hu,
Chen Wu,
Juncheng Dai,
Huizhang Li,
Jing Dong,
Meilin Wang,
Xiaoping Miao,
Yifeng Zhou,
Feng Lu, [......],
Zhiqiang Li,
Minjie Chu,
Hongxia Ma,
Jiaping Chen,
Guangfu Jin,
Wen Tan,
Tangchun Wu,
Zhengdong Zhang,
Dongxin Lin,
Hongbing Shen
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ABSTRACT: Gastric cancer, including the cardia and non-cardia types, is the second leading cause of cancer-related deaths worldwide. To identify genetic risk variants for non-cardia gastric cancer, we performed a genome-wide association study in 3,279 individuals (1,006 with non-cardia gastric cancer and 2,273 controls) of Chinese descent. We replicated significant associations in an additional 6,897 subjects (3,288 with non-cardia gastric cancer and 3,609 controls). We identified two new susceptibility loci for non-cardia gastric cancer at 5p13.1 (rs13361707 in the region including PTGER4 and PRKAA1; odds ratio (OR) = 1.41; P = 7.6 × 10(-29)) and 3q13.31 (rs9841504 in ZBTB20; OR = 0.76; P = 1.7 × 10(-9)). Imputation analyses also confirmed previously reported associations of rs2294008 and rs2976392 on 8q24, rs4072037 on 1q22 and rs13042395 on 20p13 with non-cardia gastric cancer susceptibility in the Han Chinese population.
Nature Genetics 12/2011; 43(12):1215-8. · 35.53 Impact Factor
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Lingmin Hu,
Xiangjun Zhai,
Jibin Liu,
Minjie Chu,
Shandong Pan,
Jie Jiang,
Yixin Zhang,
Hua Wang,
Jianguo Chen,
Hongbing Shen,
Zhibin Hu
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ABSTRACT: Recent genome-wide association studies showed that four single-nucleotide polymorphisms (SNPs) in human leukocyte antigen (HLA)-DP (rs3077 and rs9277535) and HLA-DQ (rs2856718 and rs7453920) were associated with chronic hepatitis B virus (HBV) infection in Japanese populations. More than 75% of hepatocellular carcinoma (HCC) patients are attributable to persistent infection of hepatitis B virus (HBV), especially in China. We genotyped these four SNPs in 1,300 HBV-positive HCC patients, 1,344 persistent HBV carriers, and 1,344 persons with HBV natural clearance from Southeast China to further test the associations of HLA-DP/DQ variants and with risk of both HBV clearance and HCC development. Logistic regression analyses showed that HLA-DQ rs2856718 significantly decreased host HCC risk, whereas three SNPs were associated with HBV clearance (HLA-DP rs9277535 as well as HLA-DQ rs7453920 and rs2856718). In addition, HLA-DP rs3077 showed an approaching significant effect on susceptibility to HBV persistent infection and HCC development when considering multiple testing adjustments. Taken together, we report, for the first time, that genetic variants in the HLA-DP and HLA-DQ loci may be marker SNPs for risk of both HBV clearance and HCC development.
Hepatology 11/2011; 55(5):1426-31. · 11.66 Impact Factor
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Jing Dong,
Zhibin Hu,
Yongqian Shu,
Shiyang Pan,
Wenping Chen,
Yi Wang, Lingmin Hu,
Yue Jiang,
Juncheng Dai,
Hongxia Ma,
Guangfu Jin,
Hongbing Shen
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ABSTRACT: To assess systematically whether potentially functional polymorphisms in DNA repair genes influence the clinical behavior of non-small-cell lung cancer (NSCLC), we examined the impact of a comprehensive panel of 218 signal nucleotide polymorphisms (SNP) in 50 candidate DNA repair genes on overall survival of NSCLC in a case-cohort of 568 lung cancer patients. SNPs associated with lung cancer prognosis primarily mapped to 14 genes in different repair pathways, and 6 SNPs were remained in the final model after multivariate stepwise Cox regression analysis: ATM rs189037; MRE11A rs11020802; ERCC2 rs1799793; MBD4 rs140693; XRCC1 rs25487, and PMS1 rs5742933. In the combined analysis of these 6 SNPs, an increasing number of unfavorable loci was associated with a poorer prognosis (P for trend: <0.0001) and patients having 2-4 unfavorable loci had a 1.99-fold elevated risk of death 95% confidence interval (CI) = 1.58-2.50, compared with those carrying 0-1 unfavorable loci, and this elevated risk was more evident among stages I-II patients (hazard ratio = 3.04, 95% CI = 1.86-4.98, P for heterogeneity: 0.07). Furthermore, a significant effect of SNPs in nucleotide excision repair pathway on lung cancer survival was observed among 185 stages III-IV patients treated with platinum-based chemotherapy without surgical operation: XPC rs2228000 (Ala499Val; P = 0.002) and ERCC1 rs11615 (Asn118Asn; P = 0.012). Our data indicate that potentially functional polymorphisms in DNA repair genes may serve as candidate prognostic markers of clinical outcome of NSCLC.
Molecular Carcinogenesis 07/2011; 51(7):546-52. · 3.16 Impact Factor
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Zhibin Hu,
Chen Wu,
Yongyong Shi,
Huan Guo,
Xueying Zhao,
Zhihua Yin,
Lei Yang,
Juncheng Dai, Lingmin Hu,
Wen Tan, [......],
Zhengdong Zhang,
Feng Chen,
Xinru Wang,
Li Jin,
Jiachun Lu,
Baosen Zhou,
Daru Lu,
Tangchun Wu,
Dongxin Lin,
Hongbing Shen
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ABSTRACT: Lung cancer is the leading cause of cancer-related deaths worldwide. To identify genetic factors that modify the risk of lung cancer in individuals of Chinese ancestry, we performed a genome-wide association scan in 5,408 subjects (2,331 individuals with lung cancer (cases) and 3,077 controls) followed by a two-stage validation among 12,722 subjects (6,313 cases and 6,409 controls). The combined analyses identified six well-replicated SNPs with independent effects and significant lung cancer associations (P < 5.0 × 10(-8)) located in TP63 (rs4488809 at 3q28, P = 7.2 × 10(-26)), TERT-CLPTM1L (rs465498 and rs2736100 at 5p15.33, P = 1.2 × 10(-20) and P = 1.0 × 10(-27), respectively), MIPEP-TNFRSF19 (rs753955 at 13q12.12, P = 1.5 × 10(-12)) and MTMR3-HORMAD2-LIF (rs17728461 and rs36600 at 22q12.2, P = 1.1 × 10(-11) and P = 6.2 × 10(-13), respectively). Two of these loci (13q12.12 and 22q12.2) were newly identified in the Chinese population. These results suggest that genetic variants in 3q28, 5p15.33, 13q12.12 and 22q12.2 may contribute to the susceptibility of lung cancer in Han Chinese.
Nature Genetics 07/2011; 43(8):792-6. · 35.53 Impact Factor
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ABSTRACT: Murine double minute 2 (MDM2) is a negative regulator of the tumor suppressor gene p53. Single nucleotide polymorphisms in MDM2 and p53 can affect patient's response to chemotherapy as well as overall survival of many cancers. This study aimed to assess the associations between polymorphisms in MDM2 and p53 and survival of non-small cell lung cancer (NSCLC) patients in Chinese. We selected and genotyped both potentially functional SNPs and tagging SNPs in MDM2 and p53 using Illumina Golden Gate platform in a cohort of 568 NSCLC patients. Associations between genotypes and NSCLC median survival time (MST) were assessed using the Kaplan-Meier method. Cox proportional hazard models were performed with the adjustment for age, stage, smoking, histology, surgical operation, and chemo- or radiotherapy status. We found that the MDM2 SNP309 (rs2279744) GT/TT genotypes were associated with a significantly worse survival (MST: 23.0 mo for GT/TT vs. 33.0 mo for GG; log-rank P = 0.028). In the multivariate Cox regression analyses, the MDM2 SNP309GT/TT genotypes were associated with a 1.42-fold [HR = 1.42, 95% confidence interval (CI), 1.09-1.84] increased risk of death of NSCLC, compared with SNP309GG genotype. MDM2 SNP309 may be used as one of the candidate biomarkers to predict NSCLC survival.
Molecular Carcinogenesis 01/2011; 50(6):433-8. · 3.16 Impact Factor
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ABSTRACT: Accumulated evidence suggested that cytotoxic T-lymphocyte antigen 4 (CTLA4) plays an important role in the negative regulation of T-cell proliferation and activation, and thus participates in antitumor immunity and cancer surveillance. Previously we reported that the CTLA4 49A/G (rs231775) single nucleotide polymorphism (SNP) was a candidate cancer susceptibility marker for breast, lung, esophageal, and gastric cancers. In the present study, we expanded our study to two infection-related cancers, namely, hepatocellular carcinoma (HCC) and cervical cancer. We genotyped rs231775 in two independent case-control studies of 864 HCC patients and 864 control subjects, and 719 cervical cancer patients and 719 control subjects. In the multivariate logistic regression models, CTLA4 +49 A/G variant genotype was associated with increased risk (AA vs GG) by 1.43-fold (95% CI = 0.94-2.17) for HCC, and 1.66-fold (95% CI = 1.13-2.44) for cervical cancer. Taken together, the results suggest that CTLA4 rs231775 may serve as a common cancer susceptibility marker.
Human immunology 09/2010; 71(9):888-91. · 2.55 Impact Factor
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ABSTRACT: Laminin-5 is required in RAS and NF-kappaB blockade induced tumorigenesis of human squamous cell carcinoma and a marker of invasiveness in cervical lesions. MicroRNA-218 (miR-218) can target laminin-5 beta3 (LAMB3), but suppressed by HPV-16 E6 protein. Therefore, we hypothesized that single nucleotide polymorphisms (SNPs) in pri-miR-218 and LAMB3 may individually and/or jointly contribute to cervical cancer carcinogenesis.
We identified one SNP rs11134527 located in pri-miR-218 sequence and one SNP rs2566 in 3'UTR of LAMB3 and genotyped these two SNPs in a case-control study of 703 cervical cancer cases and 713 cancer-free controls in Chinese women.
Logistic regression analyses showed that the pri-miR-218 rs11134527 variant homozygote GG was associated with a decreased risk of cervical cancer compared with the AA genotype (adjusted OR=0.72, 95% CI=0.52-0.99), while the LAMB3 rs2566 variant CT/TT genotypes were associated with a significantly increased risk of cervical cancer (adjusted OR=1.57, 95% CI=1.25-1.96), compared with the wild type CC genotype. A significant dose-response effect was observed between the number of risk alleles, rs11134527A and rs2566 T, and the risk of cervical cancer (P for trend=0.0006).
These findings indicate that pri-miR-218 rs11134527 and LAMB3 rs2566 may contribute to cervical cancer carcinogenesis, and further validations in diverse populations and functional characterizations are warranted.
Gynecologic Oncology 02/2010; 117(2):287-90. · 3.89 Impact Factor
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ABSTRACT: Chromosome 6p21.33, containing BAT3 and MSH5 genes, together with chromosome 6p22.1 were recently identified as susceptible regions for lung cancer in Caucasian populations. These findings interest us in assessing whether genetic variants in these regions also contribute to lung cancer risk in Chinese populations. We genotyped the most significant single nucleotide polymorphism (SNP) (rs9295740) reported in Caucasian populations at Chromosome 6p22.1 and one common potentially functional variant (rs2075789) located at exon 2 of MSH5 in a case-control study including 1009 histologically confirmed non-small cell lung cancer (NSCLC) cases and 1127 cancer-free controls in a Chinese population. We found that the distributions of genotypes of both SNPs between cases and controls were not significantly different (P = 0.624 for rs9295740 and P = 0.937 for rs2075789). Logistic regression analyses revealed neither of the two SNPs was significantly associated with altered risk of NSCLC in dominant or recessive genetic models. When we compared the combined variant genotypes (GA+AA) with the common homozygote GG, assuming a dominant genetic model, the adjusted ORs were 1.03 (95% CI = 0.86-1.25) for rs9295740 and 1.03 (95% CI = 0.85-1.25) for rs2075789. In addition, no significant associations were observed in subgroups stratified by age, gender, smoking status or histologic types. Our results indicate that the most significant SNP rs9295740 identified in Caucasians in 6p22.1 and the potentially functional SNP rs2075789 in 6p21.33, seem not applicable to Chinese populations as susceptible markers for lung cancer. Re-sequencing and fine-mapping this region, along with extensive functional evaluations, is required.
International Journal of Molecular Epidemiology and Genetics 01/2010; 1(1):11-8.
