Dongxin Lin

Publications (117)959.93 Total impact

• Article: Genome-wide association study identifies common variants in SLC39A6 associated with length of survival in esophageal squamous-cell carcinoma.

  Chen Wu, Dong Li, Weihua Jia, Zhibin Hu, Yifeng Zhou, Dianke Yu, Tong Tong, Mingrong Wang, Dongmei Lin, Yan Qiao, Yuling Zhou, Jiang Chang, Kan Zhai, Menghan Wang, Lixuan Wei, Wen Tan, Hongbing Shen, Yixin Zeng, Dongxin Lin
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  ABSTRACT: We conducted a genome-wide scan of SNPs to identify variants associated with length of survival in 1,331 individuals with esophageal squamous-cell carcinoma (ESCC), with associations validated in 2 independent sets including 1,962 individuals with this cancer. We identified rs1050631 in SLC39A6 as associated with the survival times of affected individuals, with the hazard ratio for death from ESCC in the combined sample being 1.30 (95% confidence interval (CI) = 1.19-1.43; P = 3.77 × 10(-8)). rs7242481, located in the 5' UTR of SLC39A6, disturbs a transcriptional repressor binding site and results in upregulation of SLC39A6 expression. Immunohistochemical staining of ESCC tissues showed that higher expression of SLC39A6 protein was correlated with shorter length of survival in individuals with advanced ESCC (P = 0.013). Knockdown of SLC39A6 expression suppressed proliferation and invasion in ESCC cells. These results suggest that SLC39A6 has an important role in the prognosis of ESCC and may be a potential therapeutic target.
  Nature Genetics 05/2013; · 35.53 Impact Factor
• Article: Imputation-based association analyses identify new lung cancer susceptibility variants in CDK6 and SH3RF1 and their interactions with smoking in Chinese populations.

  Qifei Deng, Huan Guo, Juncheng Dai, Lei Yang, Chen Wu, Qing Wang, Zhibin Hu, Ming Yang, Li Liu, Dianke Yu, [......], Jing Feng, Kai Teng, Jianhang Gong, Chongqi Sun, Xiaoyan Hu, Kai Zhang, Jiachun Lu, Dongxin Lin, Hongbing Shen, Tangchun Wu
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  ABSTRACT: Cell cycle regulation, apoptosis, oxidative stress, and inflammation response play critical roles in the development of smoking-induced lung cancer. However, it is still not well known whether their genetic variants are associated with lung cancer susceptibility. Here we performed imputation-based association analyses to investigate the influence of common genetic variants in these pathways and their interactions with smoking on lung cancer susceptibility. We first selected 24 042 unvalidated genetic variants in 798 genes from the imputed dataset of the previous lung cancer genome-wide association study (GWAS) in 2331 cases and 3077 controls, and then conducted additional two-stage validations in 4133 cases and 4522 controls. We found a genome-wide significant (P < 5.0×10(-8)) association for rs2282987 in CDK6 at 7q21.2 [odds ratio (OR) = 1.18, combined Padd = 2.27×10(-9)] and a consistent association for rs2706748 in SH3RF1 at 4q32.3 (OR = 1.17, combined Padd = 5.10×10(-6)). Interaction analyses showed that rs2282987 and rs2706748 interacted with both smoking status (Pinteraction were 1.04×10(-2) and 3.03×10(-2), respectively) and smoking dose (Pinteraction were 1.21×10(-2) and 5.21×10(-2), respectively) to contribute to lung cancer susceptibility in subjects aged 50 to 60 years. These results further underscore the contribution of genetic variants involved in pathways of cell cycle regulation and apoptosis to lung cancer susceptibility, and highlight gene-environment interactions in lung cancer etiology, especially in subjects aged 50 to 60 years.
  Carcinogenesis 05/2013; · 5.70 Impact Factor
• Article: The Case-Only Test for Gene-Environment Interaction is Not Uniformly Powerful: An Empirical Example.

  Chen Wu, Jiang Chang, Baoshan Ma, Xiaoping Miao, Yifeng Zhou, Yu Liu, Yun Li, Tangchun Wu, Zhibin Hu, Hongbing Shen, Weihua Jia, Yixin Zeng, Dongxin Lin, Peter Kraft
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  ABSTRACT: The case-only test has been proposed as a more powerful approach to detect gene-environment (G × E) interactions. This approach assumes that the genetic and environmental factors are independent. Although it is well known that Type I error rate will increase if this assumption is violated, it is less widely appreciated that G × E correlation can also lead to power loss. We illustrate this phenomenon by comparing the performance of the case-only test to other approaches to detect G × E interactions in a genome-wide association study (GWAS) of esophageal squamous-cell carcinoma (ESCC) in Chinese populations. Some of these approaches do not use information on the correlation between exposure and genotype (standard logistic regression), whereas others seek to use this information in a robust fashion to boost power without increasing Type I error (two-step, empirical Bayes, and cocktail methods). G × E interactions were identified involving drinking status and two regions containing genes in the alcohol metabolism pathway, 4q23 and 12q24. Although the case-only test yielded the most significant tests of G × E interaction in the 4q23 region, the case-only test failed to identify significant interactions in the 12q24 region which were readily identified using other approaches. The low power of the case-only test in the 12q24 region is likely due to the strong inverse association between the single nucleotide polymorphism (SNPs) in this region and drinking status. This example underscores the need to consider multiple approaches to detect G × E interactions, as different tests are more or less sensitive to different alternative hypotheses and violations of the G × E independence assumption.
  Genetic Epidemiology 05/2013; 37(4):402-7. · 3.44 Impact Factor
• Article: Risk Prediction of Esophageal Squamous-Cell Carcinoma with Common Genetic Variants and Life-Style Factors in Chinese Population.

  Jiang Chang, Ying Huang, Lixuan Wei, Baoshan Ma, Xiaoping Miao, Yun Li, Zhibin Hu, Dianke Yu, Weihua Jia, Yu Liu, Wen Tan, Zhonghu He, Yang Ke, Tangchun Wu, Hongbing Shen, Yixin Zeng, Chen Wu, Dongxin Lin
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  ABSTRACT: Genome-wide association studies have been identified multiple genetic variants associated with risk of esophageal squamous-cell carcinoma (ESCC) in Chinese populations. We examined whether these genetic factors, along with non-genetic factors, can contribute to ESCC risk prediction. We examined 25 single nucleotide polymorphisms (SNPs) and 4 non-genetic factors (sex, age, smoking and drinking) associated with ESCC risk in 9,805 cases and 10,493 controls from Chinese populations. Weighted genetic risk score (wGRS) was calculated and logistic regression was used to analyze the association between wGRS and ESCC risk. We calculated the area under the curve (AUC) using receiver-operation-characteristic curve analysis to measure the discrimination after adding genetic variants to the model with only non-genetic factors. Net reclassification improvement (NRI) was used to quantify the degree of correct reclassification using different models. wGRS of the combined 17 SNPs with significant marginal effect (G SNPs) increased ~4-fold ESCC risk (P=1.49×10(-164)) and the associations were significant in both drinkers and non-drinkers. However, wGRS of the 8 SNPs with significant effect in gene × drinking interaction (GE SNPs) increased ~4-fold ESCC risk only in drinkers (Pinteration=8.76×10(-41)). The AUC for a risk model with 4 non-genetic factors, 17 G SNPs, 8 GE SNPs and their interactions with drinking was 70.1%, with the significant improvement of 7.0% compared with the model with only non-genetic factors (P<.0001). Our results indicate that incorporating genetic variants, life-style factors and their interactions in ESCC risk models can be useful for identifying patients with ESCC.
  Carcinogenesis 03/2013; · 5.70 Impact Factor
• Article: Risk of Genome-Wide Association Study-Identified Genetic Variants for NHL in a Chinese Population.

  Yan Qiao, Yuling Zhou, Chen Wu, Kan Zhai, Xiaohong Han, Jieping Chen, Xiaobo Tian, Jiang Chang, Zheng Lu, Bo Zhang, Dianke Yu, Jiarui Yao, Yuankai Shi, Wen Tan, Dongxin Lin
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  ABSTRACT: Recent genome-wide association studies (GWAS) have identified 15 single nucleotide polymorphisms (SNPs) associated with Non-Hodgkin lymphoma (NHL) and its subtypes. Because the incidence and subtype portion of NHL between Chinese population and Caucasian population are substantially different, we assessed the associations of these SNPs with NHL risk in a case-control study consisting of 792 cases and 1542 controls derived from Chinese population. Odds ratios (OR) and 95% confidence intervals (CI) were computed by logistic regression. False-positive report probability (FPRP) was also assessed for significant findings. We found that the allele frequencies of the 15 SNPs in our study population significantly differed from those in Caucasian populations, with rs13397985, rs735665 and rs11083846 being extremely rare in Chinese. Only two variants (rs872071 in IRF4 and rs2647012 in HLA class II) were significantly associated with NHL risk in Chinese, with the ORs of 1.20 (95% CI, 1.05-1.38; P=0.009) and 1.20 (95% CI, 1.03-1.39; P=0.018) for per allele of rs872071 and rs2647012, respectively, calculated using an additive model. These results indicate a substantial different genetic background for susceptibility to NHL among the different ethnic populations.
  Carcinogenesis 03/2013; · 5.70 Impact Factor
• Article: A Genome-Wide Association Study for Serum Bilirubin Levels and Gene-Environment Interaction in a Chinese Population.

  Xiayun Dai, Chen Wu, Yunfeng He, Lixuan Gui, Li Zhou, Huan Guo, Jing Yuan, Binyao Yang, Jun Li, Qifei Deng, [......], Die Hu, Jiang Zhu, Xinwen Min, Mingjian Lang, Dongfeng Li, Handong Yang, Frank B Hu, Dongxin Lin, Tangchun Wu, Meian He
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  ABSTRACT: Bilirubin is an effective antioxidant and is influenced by both genetic and environmental factors. Recent genome-wide association studies (GWAS) have identified multiple loci affecting serum total bilirubin levels. However, most of the studies were conducted in European populations and little attention has been devoted either to genetic variants associated with direct and indirect bilirubin levels or to the gene-environment interactions on bilirubin levels. In this study, a two-stage GWAS was performed to identify genetic variants associated with all types of bilirubin levels in 10,282 Han Chinese individuals. Gene-environment interactions were further examined. Briefly, two previously reported loci, UGT1A1 on 2q37 (rs6742078 and rs4148323, combined P = 1.44 × 10(-89) and P = 5.05 × 10(-69) , respectively) and SLCO1B3 on 12p12 (rs2417940, combined P = 6.93 × 10(-19) ) were successfully replicated. The two loci explained 9.2% and 0.9% of the total variations of total bilirubin levels, respectively. Ethnic genetic differences were observed between Chinese and European populations. More importantly, a significant interaction was found between rs2417940 in SLCO1B3 gene and smoking on total bilirubin levels (P = 1.99 × 10(-3) ). Single nucleotide polymorphism (SNP) rs2417940 had stronger effects on total bilirubin levels in nonsmokers than in smokers, suggesting that the effects of SLCO1B3 genotype on bilirubin levels were partly dependent on smoking status. Consistent associations and interactions were observed for serum direct and indirect bilirubin levels.
  Genetic Epidemiology 01/2013; · 3.44 Impact Factor
• Source

  Available from: Guangwen Cao

  Article: Identification of common variants in BRCA2 and MAP2K4 for susceptibility to sporadic pancreatic cancer.

  Liming Huang, Chen Wu, Dianke Yu, Chengfeng Wang, Xu Che, Xiaoping Miao, Kan Zhai, Jiang Chang, Guoliang Jiang, Xianghong Yang, [......], Menghong Sun, Wei Cao, Jun Gao, Ying Ma, Xiongwei Zheng, Siu Tim Cheung, Yongfeng Jia, Wen Tan, Tangchun Wu, Dongxin Lin
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  ABSTRACT: Germline mutations in genes that cause hereditary syndromes are highly predisposed to familial pancreatic cancer. However, genetic susceptibility to sporadic pancreatic cancer is largely uncovered. We conducted a two-stage association study on pancreatic cancer that included 981 cases and 1,991 controls in the first stage followed by a second stage (2,603 cases and 2,877 controls). Using an approach based on candidate genes whose roles in pancreatic cancer have been well-known, we identified two new susceptibility loci. rs11571836 located in the BRCA2 3'-untranslated region was significantly associated with lower expression of BRCA2 transcript and increased pancreatic cancer risk [odds ratio (OR)=1.30, 95% confidence interval (CI)=1.14-1.47, P=7.64x10-5] in a recessive manner. rs12939944 located in the MAP2K4 intron was associated with decreased risk (OR=0.82, 95% CI=0.74-0.91, P=0.0001) in a dominant manner. Our results demonstrate for the first time that common variants in BRCA2 and MAP2K4 are susceptibility to sporadic pancreatic cancer.
  Carcinogenesis 01/2013; · 5.70 Impact Factor
• Article: A genome wide association study of genetic loci that influence tumour biomarkers cancer antigen 19-9, carcinoembryonic antigen and α fetoprotein and their associations with cancer risk.

  Meian He, Chen Wu, Jianfeng Xu, Huan Guo, Handong Yang, Xiaomin Zhang, Jielin Sun, Dianke Yu, Li Zhou, Tao Peng, [......], Weimin Fang, Yuan Liang, Yun Zhai, Weihong Chen, Xiaoping Miao, Gangqiao Zhou, Frank B Hu, Dongxin Lin, Zengnan Mo, Tangchun Wu
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  ABSTRACT: OBJECTIVE: Tumour biomarkers are used as indicators for cancer screening and as predictors for therapeutic responses and prognoses in cancer patients. We aimed to identify genetic loci that influence concentrations of cancer antigen 19-9 (CA19-9), carcinoembryonic antigen (CEA) and α fetoprotein (AFP), and investigated the associations between the significant single nucleotide polymorphisms (SNPs) with risks of oesophageal squamous cell (OSCC), pancreatic and hepatocellular cancers. DESIGN: We carried out a genome wide association study on plasma CA19-9, CEA and AFP concentrations in 3451 healthy Han Chinese and validated the results in 10 326 individuals. Significant SNPs were further investigated in three case control studies (2031 OSCC cases and 2044 controls; 981 pancreatic cancer cases and 1991 controls; and 348 hepatocellular cancer cases and 359 controls). RESULTS: The analyses showed association peaks on three genetic loci for CA19-9 (FUT6-FUT3 at 19p13.3, FUT2-CA11 at 19q13.3 and B3GNT3 at 19p13.1; p=1.16×10(-13)-3.30×10(-290)); four for CEA (ABO at 9q34.2, FUT6 at 19p13.3, FUT2 at 19q13.3 and FAM3B at 21q22.3; p=3.33×10(-22)-5.81×10(-209)); and two for AFP (AFP at 4q11-q13 and HISPPD2A at 15q15.3; p=3.27×10(-18) and 1.28×10(-14)). These explained 17.14% of the variations in CA19-9, 8.95% in CEA and 0.57% in AFP concentrations. Significant ABO variants were also associated with risk of OSCC and pancreatic cancers, and AFP variants with risk of hepatocellular cancer (p<0.05). CONCLUSIONS: This study identified several loci associated with CA19-9, CEA and AFP concentrations. The ABO variants were associated with risk of OSCC and pancreatic cancers and AFP variants with risk of hepatocellular cancer.
  Gut 01/2013; · 10.11 Impact Factor
• Article: Genome-wide association study identifies a novel susceptibility locus at 12q23.1 for lung squamous cell carcinoma in han chinese.

  Jing Dong, Guangfu Jin, Chen Wu, Huan Guo, Baosen Zhou, Jiachun Lv, Daru Lu, Yongyong Shi, Yongqian Shu, Lin Xu, [......], Ying Yan, Jibin Liu, Christopher I Amos, Feng Chen, Wen Tan, Li Jin, Tangchun Wu, Zhibin Hu, Dongxin Lin, Hongbing Shen
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  ABSTRACT: Adenocarcinoma (AC) and squamous cell carcinoma (SqCC) are two major histological subtypes of lung cancer. Genome-wide association studies (GWAS) have made considerable advances in the understanding of lung cancer susceptibility. Obvious heterogeneity has been observed between different histological subtypes of lung cancer, but genetic determinants in specific to lung SqCC have not been systematically investigated. Here, we performed the GWAS analysis specifically for lung SqCC in 833 SqCC cases and 3,094 controls followed by a two-stage replication in additional 2,223 lung SqCC cases and 6,409 controls from Chinese populations. We found that rs12296850 in SLC17A8-NR1H4 gene region at12q23.1 was significantly associated with risk of lung SqCC at genome-wide significance level [additive model: odds ratio (OR) = 0.78, 95% confidence interval (CI) = 0.72-0.84, P = 1.19×10(-10)]. Subjects carrying AG or GG genotype had a 26% (OR = 0.74, 95% CI = 0.67-0.81) or 32% (OR = 0.68, 95% CI = 0.56-0.83) decreased risk of lung SqCC, respectively, as compared with AA genotype. However, we did not observe significant association between rs12296850 and risk of lung AC in a total of 4,368 cases with lung AC and 9,486 controls (OR = 0.96, 95% CI = 0.90-1.02, P = 0.173). These results indicate that genetic variations on chromosome 12q23.1 may specifically contribute to lung SqCC susceptibility in Chinese population.
  PLoS Genetics 01/2013; 9(1):e1003190. · 8.69 Impact Factor
• Article: Pathway analysis for genome-wide association study of lung cancer in han chinese population.

  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
• Article: There Is No Association between MicroRNA Gene Polymorphisms and Risk of Triple Negative Breast Cancer in a Chinese Han Population.

  Fei Ma, Ping Zhang, Dongxin Lin, Dianke Yu, Peng Yuan, Jiayu Wang, Yin Fan, Binghe Xu
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  ABSTRACT: Triple-negative breast cancer (TNBC) is defined by the lack of the expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). It is characterized by aggressive behavior, poor prognosis and lack of targeted therapies. MicroRNA (miRNA) as a novel modulator of gene expression has played an important regulatory role in the malignancy. Dysregulation and/or mutation of the miRNAs may also contribute to the TNBC susceptibility since it is associated with the expression of ER, PR and HER2. Single nucleotide polymorphisms (SNPs) in miRNAs may be extremely relevant for TNBC. We tried to validate the hypothesis that genetic variations in miRNA are associated with TNBC development, and identify candidate biomarkers for TNBC susceptibility and clinical treatment. We screened the genetic variants in all miRNA genes listed in the public database miRBase and NCBI. A total of 23 common SNPs in 22 miRNAs, which tagged the known common variants in the Chinese Han people with a minor allele frequency greater than 0.05, were genotyped. This case-control study involved 191 patients with TNBC and 192 healthy female controls. Frequencies of SNPs were compared between cases and controls to identify the SNPs associated with TNBC susceptibility. No significant association was found between TNBC risk and the SNPs in the miRNA genes in the Chinese Han people (P>0.05), but this warrants further studies.
  PLoS ONE 01/2013; 8(3):e60195. · 4.09 Impact Factor
• Article: Evidence of associations of APOBEC3B gene deletion with susceptibility to persistent HBV infection and hepatocellular carcinoma.

  Tongwen Zhang, Jianqiang Cai, Jiang Chang, Dianke Yu, Chen Wu, Tao Yan, Kan Zhai, Xinyu Bi, Hong Zhao, Jian Xu, Wen Tan, Chunfeng Qu, Dongxin Lin
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  ABSTRACT: APOBEC3s are a family of cytidine deaminases involved in innate cellular immunity against virus including hepatitis B virus (HBV). A germline deletion across APOBEC3A and APOBEC3B (A3B) genes results in complete removal of the A3B coding region and destroys A3B expression. To determine whether this deletion affects susceptibility to HBV infection and HBV-related hepatocellular carcinoma (HCC), A3B genotypes were analyzed in 1,124 individuals with HCC, 510 individuals with persistent HBV infection and 826 healthy controls and the association was estimated by odds ratio (OR) and 95% confidence interval (CI) computed by logistic regression. We also examined the effects of APOBEC3B on HBV genome hypermutation and replication in HCC cells. We observed a significantly higher frequency of the A3B deletion allele in persistent HBV carriers (33.3%; P=0.0015) and HCC patients (37.9%; P=1.28×10(-11)) compared with that in controls (27.5%). An increased risk for persistent HBV infection (OR=1.35, 95% CI, 1.03-1.77) and HCC development (OR=1.90, 95% CI, 1.58-2.28) was associated with at least one A3B deletion allele (+/- or -/- genotype) compared with the +/+ genotype. Transfection of A3B in HepG2 cells caused a substantial reduction of HBV RNA levels and G→A hypermutation in HBV genome. Interestingly, a cytidine deaminase null mutant of A3B (E255A) also inhibited HBV RNA production although it was unable to edit HBV. These results suggest that deletion of A3B attenuates HBV clearance, which in turn may result in persistent HBV infection and increased risk for developing HCC. Further studies are needed to verify our findings.
  Human Molecular Genetics 12/2012; · 7.64 Impact Factor
• Source

  Available from: Keitaro Matsuo

  Article: Genome-wide association analysis identifies new lung cancer susceptibility loci in never-smoking women in Asia.

  Qing Lan, Chao A Hsiung, Keitaro Matsuo, Yun-Chul Hong, Adeline Seow, Zhaoming Wang, H Dean Hosgood, Kexin Chen, Jiu-Cun Wang, Nilanjan Chatterjee, [......], Hsien-Chih Lin, Tangchun Wu, Yi-Long Wu, Pan-Chyr Yang, Baosen Zhou, Min-Ho Shin, Joseph F Fraumeni, Dongxin Lin, Stephen J Chanock, Nathaniel Rothman
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  ABSTRACT: To identify common genetic variants that contribute to lung cancer susceptibility, we conducted a multistage genome-wide association study of lung cancer in Asian women who never smoked. We scanned 5,510 never-smoking female lung cancer cases and 4,544 controls drawn from 14 studies from mainland China, South Korea, Japan, Singapore, Taiwan and Hong Kong. We genotyped the most promising variants (associated at P < 5 × 10(-6)) in an additional 1,099 cases and 2,913 controls. We identified three new susceptibility loci at 10q25.2 (rs7086803, P = 3.54 × 10(-18)), 6q22.2 (rs9387478, P = 4.14 × 10(-10)) and 6p21.32 (rs2395185, P = 9.51 × 10(-9)). We also confirmed associations reported for loci at 5p15.33 and 3q28 and a recently reported finding at 17q24.3. We observed no evidence of association for lung cancer at 15q25 in never-smoking women in Asia, providing strong evidence that this locus is not associated with lung cancer independent of smoking.
  Nature Genetics 11/2012; · 35.53 Impact Factor
• Article: Genetic Variants at 6p21.1 and 7p15.3 Are Associated with Risk of Multiple Cancers in Han Chinese.

  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
• Article: Genome-wide association analyses of esophageal squamous cell carcinoma in Chinese identify multiple susceptibility loci and gene-environment interactions.

  Chen Wu, Peter Kraft, Kan Zhai, Jiang Chang, Zhaoming Wang, Yun Li, Zhibin Hu, Zhonghu He, Weihua Jia, Christian C Abnet, [......], Ti Ding, Wen Tan, Alisa M Goldstein, Tangchun Wu, Hongbing Shen, Yang Ke, Yixin Zeng, Stephen J Chanock, Philip R Taylor, Dongxin Lin
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  ABSTRACT: We conducted a genome-wide association study (GWAS) and a genome-wide gene-environment interaction analysis of esophageal squamous-cell carcinoma (ESCC) in 2,031 affected individuals (cases) and 2,044 controls with independent validation in 8,092 cases and 8,620 controls. We identified nine new ESCC susceptibility loci, of which seven, at chromosomes 4q23, 16q12.1, 17q21, 22q12, 3q27, 17p13 and 18p11, had a significant marginal effect (P = 1.78 × 10(-39) to P = 2.49 × 10(-11)) and two of which, at 2q22 and 13q33, had a significant association only in the gene-alcohol drinking interaction (gene-environment interaction P (P(G × E)) = 4.39 × 10(-11) and P(G × E) = 4.80 × 10(-8), respectively). Variants at the 4q23 locus, which includes the ADH cluster, each had a significant interaction with alcohol drinking in their association with ESCC risk (P(G × E) = 2.54 × 10(-7) to P(G × E) = 3.23 × 10(-2)). We confirmed the known association of the ALDH2 locus on 12q24 to ESCC, and a joint analysis showed that drinkers with both of the ADH1B and ALDH2 risk alleles had a fourfold increased risk for ESCC compared to drinkers without these risk alleles. Our results underscore the direct genetic contribution to ESCC risk, as well as the genetic contribution to ESCC through interaction with alcohol consumption.
  Nature Genetics 09/2012; 44(10):1090-7. · 35.53 Impact Factor
• Article: Multi-loci analysis reveals the importance of genetic variations in sensitivity of platinum-based chemotherapy in non-small-cell lung cancer.

  Li Liu, Jing Wu, Rong Zhong, Chen Wu, Li Zou, Beifang Yang, Wei Chen, Beibei Zhu, Shengyu Duan, Dianke Yu, Wen Tan, Shaofa Nie, Dongxin Lin, Xiaoping Miao
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  ABSTRACT: Polymorphisms in DNA repair and apoptotic pathways may cause variations in chemosensitivity of non-small-cell lung cancer (NSCLC) through complex gene-gene and gene-environment interactions. A total of 200 advanced NSCLC patients who received platinum-based chemotherapies were recruited. The short-term clinical outcomes were classified as chemosensitive group, including complete remission (CR) and partial remission (PR), and chemoresistant group, namely stable disease (SD) and progression disease (PD) at the end of treatment. We applied multifactor dimensionality reduction (MDR), classification and regression tree (CART) and traditional logistic regression (LR) to explore high-order gene-gene and gene-environment interactions among 11 functional single nucleotide polymorphisms (SNPs), smoking status, cancer stages and treatment regimens in the response to chemotherapy. Multi-loci analyses consistently indicated that interactions among XRCC1 Arg194Trp, XPC PAT, FAS G-1377A, and FASL T-844C were associated with sensitivity to platinum-based chemotherapy. In MDR analysis, the four-factor model yielded the highest test accuracy of 0.72 (permutation P = 0.001). In CART analysis, these four SNPs were the determinant nodes of the growth of regression tree. Patients carrying XRCC1 Arg194Arg, FAS-1377GG, and FASL-844T allele displayed completely no response to platinum, whereas patients with XRCC1 194Trp allele and XPC PAT +/+ had 68.8% response rate to platinum. In LR analysis, a significant gene-dosage effect was detected along with the increasing number of favorable genotypes of these four polymorphisms (P(trend)  = 0.00002). Multi-loci analysis reveals the importance of genetic variations involved in DNA repair and apoptotic pathways in sensitivity of platinum-based chemotherapy in NSCLC. © 2012 Wiley Periodicals, Inc.
  Molecular Carcinogenesis 07/2012; · 3.16 Impact Factor
• Article: Association analyses identify multiple new lung cancer susceptibility loci and their interactions with smoking in the Chinese population.

  Jing Dong, Zhibin Hu, Chen Wu, Huan Guo, Baosen Zhou, Jiachun Lv, Daru Lu, Kexin Chen, Yongyong Shi, Minjie Chu, [......], Yuxia Zhao, Haibo Zhang, Ying Yan, Christopher I Amos, Feng Chen, Wen Tan, Li Jin, Tangchun Wu, Dongxin Lin, Hongbing Shen
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  ABSTRACT: To find additional susceptibility loci for lung cancer, we tested promising associations from our previous genome-wide association study (GWAS) of lung cancer in the Chinese population in an extended validation sample size of 7,436 individuals with lung cancer (cases) and 7,483 controls. We found genome-wide significant (P < 5.0 × 10(-8)) evidence for three additional lung cancer susceptibility loci at 10p14 (rs1663689, close to GATA3, P = 2.84 × 10(-10)), 5q32 (rs2895680 in PPP2R2B-STK32A-DPYSL3, P = 6.60 × 10(-9)) and 20q13.2 (rs4809957 in CYP24A1, P = 1.20 × 10(-8)). We also found consistent associations for rs247008 at 5q31.1 (IL3-CSF2-P4HA2, P = 7.68 × 10(-8)) and rs9439519 at 1p36.32 (AJAP1-NPHP4, P = 3.65 × 10(-6)). Four of these loci showed evidence for interactions with smoking dose (P = 1.72 × 10(-10), P = 5.07 × 10(-3), P = 6.77 × 10(-3) and P = 4.49 × 10(-2) for rs2895680, rs4809957, rs247008 and rs9439519, respectively). These results advance our understanding of lung cancer susceptibility and highlight potential pathways that integrate genetic variants and smoking in the development of lung cancer.
  Nature Genetics 07/2012; 44(8):895-9. · 35.53 Impact Factor
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  Available from: Jun Wang

  Article: GWAS identifies novel susceptibility loci on 6p21.32 and 21q21.3 for hepatocellular carcinoma in chronic hepatitis B virus carriers.

  Shengping Li, Ji Qian, Yuan Yang, Wanting Zhao, Juncheng Dai, Jin-Xin Bei, Jia Nee Foo, Paul J McLaren, Zhiqiang Li, Jingmin Yang, [......], Hongbing Shen, Lin He, Paul I W de Bakker, Hongyang Wang, Yi-Xin Zeng, Mengchao Wu, Zhibin Hu, Yongyong Shi, Jianjun Liu, Weiping Zhou
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  ABSTRACT: Genome-wide association studies (GWAS) have recently identified KIF1B as susceptibility locus for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). To further identify novel susceptibility loci associated with HBV-related HCC and replicate the previously reported association, we performed a large three-stage GWAS in the Han Chinese population. 523,663 autosomal SNPs in 1,538 HBV-positive HCC patients and 1,465 chronic HBV carriers were genotyped for the discovery stage. Top candidate SNPs were genotyped in the initial validation samples of 2,112 HBV-positive HCC cases and 2,208 HBV carriers and then in the second validation samples of 1,021 cases and 1,491 HBV carriers. We discovered two novel associations at rs9272105 (HLA-DQA1/DRB1) on 6p21.32 (OR = 1.30, P = 1.13×10⁻¹⁹) and rs455804 (GRIK1) on 21q21.3 (OR = 0.84, P = 1.86×10⁻⁸), which were further replicated in the fourth independent sample of 1,298 cases and 1,026 controls (rs9272105: OR = 1.25, P = 1.71×10⁻⁴; rs455804: OR = 0.84, P = 6.92×10⁻³). We also revealed the associations of HLA-DRB1*0405 and 0901*0602, which could partially account for the association at rs9272105. The association at rs455804 implicates GRIK1 as a novel susceptibility gene for HBV-related HCC, suggesting the involvement of glutamate signaling in the development of HBV-related HCC.
  PLoS Genetics 07/2012; 8(7):e1002791. · 8.69 Impact Factor
• Article: Increased risk of lung cancer associated with a functionally impaired polymorphic variant of the human DNA glycosylase NEIL2.

  Sanjib Dey, Amit K Maiti, Muralidhar L Hegde, Pavana M Hegde, Istvan Boldogh, Partha S Sarkar, Sherif Z Abdel-Rahman, Altaf H Sarker, Bo Hang, Jingwu Xie, Alan E Tomkinson, Mian Zhou, Binghui Shen, Guanghai Wang, Chen Wu, Dianke Yu, Dongxin Lin, Victor Cardenas, Tapas K Hazra
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  ABSTRACT: Human NEIL2, one of five oxidized base-specific DNA glycosylases, is unique in preferentially repairing oxidative damage in transcribed genes. Here we show that depletion of NEIL2 causes a 6-7-fold increase in spontaneous mutation frequency in the HPRT gene of the V79 Chinese hamster lung cell line. This prompted us to screen for NEIL2 variants in lung cancer patients' genomic DNA. We identified several polymorphic variants, among which R103Q and R257L were frequently observed in lung cancer patients. We then characterized these variants biochemically, and observed a modest decrease in DNA glycosylase activity relative to the wild type (WT) only with the R257L mutant protein. However, in reconstituted repair assays containing WT NEIL2 or its R257L and R103Q variants together with other DNA base excision repair (BER) proteins (PNKP, Polβ, Lig IIIα and XRCC1) or using NEIL2-FLAG immunocomplexes, an ~5-fold decrease in repair was observed with the R257L variant compared to WT or R103Q NEIL2, apparently due to the R257L mutant's lower affinity for other repair proteins, particularly Polβ. Notably, increased endogenous DNA damage was observed in NEIL2 variant (R257L)-expressing cells relative to WT cells. Taken together, our results suggest that the decreased DNA repair capacity of the R257L variant can induce mutations that lead to lung cancer development.
  DNA repair 04/2012; 11(6):570-8. · 4.20 Impact Factor
• Article: Genetic variant in TP63 on locus 3q28 is associated with risk of lung adenocarcinoma among never-smoking females in Asia.

  H Dean Hosgood, Wen-Chang Wang, Yun-Chul Hong, Jiu-Cun Wang, Kexin Chen, I-Shou Chang, Chien-Jen Chen, Daru Lu, Zhihua Yin, Chen Wu, [......], Fang-Yu Tsai, Pan-Chyr Yang, Joseph F Fraumeni, Adeline Seow, Dongxin Lin, Baosen Zhou, Stephen Chanock, Chao Agnes Hsiung, Nathaniel Rothman, Qing Lan
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  ABSTRACT: A recent genome-wide association study (GWAS) of subjects from Japan and South Korea reported a novel association between the TP63 locus on chromosome 3q28 and risk of lung adenocarcinoma (p = 7.3 × 10(-12)); however, this association did not achieve genome-wide significance (p ≤ 10(-7)) among never-smoking males or females. To determine if this association with lung cancer risk is independent of tobacco use, we genotyped the TP63 SNPs reported by the previous GWAS (rs10937405 and rs4488809) in 3,467 never-smoking female lung cancer cases and 3,787 never-smoking female controls from 10 studies conducted in Taiwan, Mainland China, South Korea, and Singapore. Genetic variation in rs10937405 was associated with risk of lung adenocarcinoma [n = 2,529 cases; p = 7.1 × 10(-8); allelic risk = 0.80, 95% confidence interval (CI) = 0.74-0.87]. There was also evidence of association with squamous cell carcinoma of the lung (n = 302 cases; p = 0.037; allelic risk = 0.82, 95% CI = 0.67-0.99). Our findings provide strong evidence that genetic variation in TP63 is associated with the risk of lung adenocarcinoma among Asian females in the absence of tobacco smoking.
  Human Genetics 02/2012; 131(7):1197-203. · 5.07 Impact Factor