Browsing by Author "Wang, Li-E"
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Item Open Access A functional NQO1 609C>T polymorphism and risk of gastrointestinal cancers: a meta-analysis.(PloS one, 2012-01-17) Yu, Hongping; Liu, Hongliang; Wang, Li-E; Wei, QingyiThe functional polymorphism (rs1800566) in the NQO1 gene, a 609C>T substitution, leading to proline-to-serine amino-acid and enzyme activity changes, has been implicated in cancer risk, but individually published studies showed inconclusive results.We performed a meta-analysis of 20 publications with a total of 5,491 cases and 5,917 controls, mainly on gastrointestinal (GI) cancers. We summarized the data on the association between the NQO1 609C>T polymorphism and risk of GI cancers and performed subgroup analyses by ethnicity, cancer site, and study quality. We found that the variant CT heterozygous and CT/TT genotypes of the NQO1 609 C>T polymorphism were associated with a modestly increased risk of GI cancers (CT vs. CC: OR = 1.10, 95% CI = 1.01 - 1.19, P(heterogeneity) = 0.27, I(2) = 0.15; CT/TT vs. CC: OR = 1.11, 95%CI = 1.02 - 1.20, P(heterogeneity) = 0.14; I(2) = 0.27). Following further stratified analyses, the increased risk was only observed in subgroups of Caucasians, colorectal cancer in Caucasians, and high quality studies.This meta-analysis suggests that the NQO1 609T allele is a low-penetrance risk factor for GI cancers. Although the effect on GI cancers may be modified by ethnicity and cancer sites, small sample seizes of the subgroup analyses suggest that further larger studies are needed, especially for non-colorectal GI cancers in Caucasians and GI cancers in Asians.Item Open Access A genome-wide association study of upper aerodigestive tract cancers conducted within the INHANCE consortium.(PLoS genetics, 2011-03-17) McKay, James D; Truong, Therese; Gaborieau, Valerie; Chabrier, Amelie; Chuang, Shu-Chun; Byrnes, Graham; Zaridze, David; Shangina, Oxana; Szeszenia-Dabrowska, Neonila; Lissowska, Jolanta; Rudnai, Peter; Fabianova, Eleonora; Bucur, Alexandru; Bencko, Vladimir; Holcatova, Ivana; Janout, Vladimir; Foretova, Lenka; Lagiou, Pagona; Trichopoulos, Dimitrios; Benhamou, Simone; Bouchardy, Christine; Ahrens, Wolfgang; Merletti, Franco; Richiardi, Lorenzo; Talamini, Renato; Barzan, Luigi; Kjaerheim, Kristina; Macfarlane, Gary J; Macfarlane, Tatiana V; Simonato, Lorenzo; Canova, Cristina; Agudo, Antonio; Castellsagué, Xavier; Lowry, Ray; Conway, David I; McKinney, Patricia A; Healy, Claire M; Toner, Mary E; Znaor, Ariana; Curado, Maria Paula; Koifman, Sergio; Menezes, Ana; Wünsch-Filho, Victor; Neto, José Eluf; Garrote, Leticia Fernández; Boccia, Stefania; Cadoni, Gabriella; Arzani, Dario; Olshan, Andrew F; Weissler, Mark C; Funkhouser, William K; Luo, Jingchun; Lubiński, Jan; Trubicka, Joanna; Lener, Marcin; Oszutowska, Dorota; Schwartz, Stephen M; Chen, Chu; Fish, Sherianne; Doody, David R; Muscat, Joshua E; Lazarus, Philip; Gallagher, Carla J; Chang, Shen-Chih; Zhang, Zuo-Feng; Wei, Qingyi; Sturgis, Erich M; Wang, Li-E; Franceschi, Silvia; Herrero, Rolando; Kelsey, Karl T; McClean, Michael D; Marsit, Carmen J; Nelson, Heather H; Romkes, Marjorie; Buch, Shama; Nukui, Tomoko; Zhong, Shilong; Lacko, Martin; Manni, Johannes J; Peters, Wilbert HM; Hung, Rayjean J; McLaughlin, John; Vatten, Lars; Njølstad, Inger; Goodman, Gary E; Field, John K; Liloglou, Triantafillos; Vineis, Paolo; Clavel-Chapelon, Francoise; Palli, Domenico; Tumino, Rosario; Krogh, Vittorio; Panico, Salvatore; González, Carlos A; Quirós, J Ramón; Martínez, Carmen; Navarro, Carmen; Ardanaz, Eva; Larrañaga, Nerea; Khaw, Kay-Tee; Key, Timothy; Bueno-de-Mesquita, H Bas; Peeters, Petra HM; Trichopoulou, Antonia; Linseisen, Jakob; Boeing, Heiner; Hallmans, Göran; Overvad, Kim; Tjønneland, Anne; Kumle, Merethe; Riboli, Elio; Välk, Kristjan; Vooder, Tõnu; Metspalu, Andres; Zelenika, Diana; Boland, Anne; Delepine, Marc; Foglio, Mario; Lechner, Doris; Blanché, Hélène; Gut, Ivo G; Galan, Pilar; Heath, Simon; Hashibe, Mia; Hayes, Richard B; Boffetta, Paolo; Lathrop, Mark; Brennan, PaulGenome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in susceptibility to etiologically complex disease. We conducted a GWAS to identify common genetic variation involved in susceptibility to upper aero-digestive tract (UADT) cancers. Genome-wide genotyping was carried out using the Illumina HumanHap300 beadchips in 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls. The 19 top-ranked variants were investigated further in an additional 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies participating in the INHANCE consortium. Five common variants presented evidence for significant association in the combined analysis (p ≤ 5 × 10⁻⁷). Two novel variants were identified, a 4q21 variant (rs1494961, p = 1×10⁻⁸) located near DNA repair related genes HEL308 and FAM175A (or Abraxas) and a 12q24 variant (rs4767364, p =2 × 10⁻⁸) located in an extended linkage disequilibrium region that contains multiple genes including the aldehyde dehydrogenase 2 (ALDH2) gene. Three remaining variants are located in the ADH gene cluster and were identified previously in a candidate gene study involving some of these samples. The association between these three variants and UADT cancers was independently replicated in 5,092 UADT cancer cases and 6,794 controls non-overlapping samples presented here (rs1573496-ADH7, p = 5 × 10⁻⁸); rs1229984-ADH1B, p = 7 × 10⁻⁹; and rs698-ADH1C, p = 0.02). These results implicate two variants at 4q21 and 12q24 and further highlight three ADH variants in UADT cancer susceptibility.Item Open Access Association between a rare novel TP53 variant (rs78378222) and melanoma, squamous cell carcinoma of head and neck and lung cancer susceptibility in non-Hispanic Whites.(Journal of cellular and molecular medicine, 2013-07) Guan, Xiaoxiang; Wang, Li-E; Liu, Zhensheng; Sturgis, Erich M; Wei, QingyiRecently, several studies have investigated the association between a newly reported rare functional single nucleotide polymorphism (SNP) in TP53 (rs78378222) and cancer risk, but generated inconsistent findings. The present study further investigated this association with risk of melanoma, squamous cell carcinoma of head and neck (SCCHN) and lung cancer. Using volunteers of non-Hispanic Whites recruited for three large case-control studies, we genotyped the TP53 rs78378222 SNP in 1329 patients with melanoma, 1096 with SCCHN, 1013 with lung cancer and 3000 cancer-free controls. Overall, we did not observe any variant homozygotes in this study population, nor significant associations between the TP53 rs78378222AC genotype or C allele and risk for melanoma (P = 0.680 and 0.682 respectively) and lung cancer (P = 0.379 and 0.382 respectively), but a protection against SCCHN (P = 0.008 and 0.008 respectively), compared with the AA genotype or A allele. An additional meta-analysis including 19,423 cancer patients and 54,050 controls did not support such a risk association either. Our studies did not provide statistical evidence of an association between this rare TP53 variant and increased risk of melanoma, nor of lung cancer, but a possible protection against SCCHN.Item Open Access Association between novel PLCE1 variants identified in published esophageal cancer genome-wide association studies and risk of squamous cell carcinoma of the head and neck.(BMC cancer, 2011-06-20) Ma, Hongxia; Wang, Li-E; Liu, Zhensheng; Sturgis, Erich M; Wei, QingyiPhospholipase C epsilon 1 (PLCE1) (an effector of Ras) belonging to the phospholipase family plays crucial roles in carcinogenesis and progression of several cancers, including squamous cell carcinoma of the head and neck (SCCHN). A single nucleotide polymorphism (SNP, rs2274223) in PLCE1 has been identified as a novel susceptibility locus in genome-wide association studies (GWAS) of esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinoma (GCA) that share similar risk factors with SCCHN. Therefore, we investigated the association between potentially functional SNPs in PLCE1 and susceptibility to SCCHN.We genotyped three potentially functional SNPs (rs2274223A/G, rs3203713A/G and rs11599672T/G) of PLCE1 in 1,098 SCCHN patients and 1,090 controls matched by age and sex in a non-Hispanic white population.Although none of three SNPs was alone significantly associated with overall risk of SCCHN, their combined effects of risk alleles (rs2274223G, rs3203713G and rs11599672G) were found to be associated with risk of SCCHN in a locus-dose effect manner (Ptrend=0.046), particularly for non-oropharyngeal tumors (Ptrend=0.017); specifically, rs2274223 was associated with a significantly increased risk (AG vs. AA: adjusted OR=1.29, 95% CI=1.01-1.64; AG/GG vs. AA: adjusted OR=1.30, 95% CI=1.03-1.64), while rs11599672 was associated with a significantly decreased risk (GG vs. TT: adjusted OR=0.54, 95% CI=0.34-0.86; TG/GG vs. TT: adjusted OR=0.76, 95% CI=0.61-0.95).Our findings suggest that PLCE1 variants may have an effect on risk of SCCHN associated with tobacco and alcohol exposure, particularly for those tumors arising at non-oropharyngeal sites. These findings, although need to be validated by larger studies, are consistent with those in esophageal and gastric cancers.Item Open Access Association between single nucleotide polymorphisms in ERCC4 and risk of squamous cell carcinoma of the head and neck.(PloS one, 2012-01) Yu, Hongping; Liu, Zhensheng; Huang, Yu-Jing; Yin, Ming; Wang, Li-E; Wei, QingyiExcision repair cross-complementation group 4 gene (ERCC4/XPF) plays an important role in nucleotide excision repair and participates in removal of DNA interstrand cross-links and DNA double-strand breaks. Single nucleotide polymorphisms (SNPs) in ERCC4 may impact repair capacity and affect cancer susceptibility.In this case-control study, we evaluated associations of four selected potentially functional SNPs in ERCC4 with risk of squamous cell carcinoma of the head and neck (SCCHN) in 1,040 non-Hispanic white patients with SCCHN and 1,046 cancer-free matched controls. We found that the variant GG genotype of rs2276466 was significantly associated with a decreased risk of SCCHN (OR = 0.69, 95% CI 0.50-0.96), and that the variant TT genotype of rs3136038 showed a borderline significant decreased risk with SCCHN (OR = 0.76, 95% CI: 0.58-1.01) in the recessive model. Such protective effects were more evident in oropharyngeal cancer (OR = 0.61, 95% CI: 0.40-0.92 for rs2276466; OR = 0.69, 95% CI: 0.48-0.98 for rs3136038). No significant associations were found for the other two SNPs (rs1800067 and rs1799798). In addition, individuals with the rs2276466 GG or with the rs3136038 TT genotypes had higher levels of ERCC4 mRNA expression than those with the corresponding wild-type genotypes in 90 Epstein-Barr virus-transformed lymphoblastoid cell lines derived from Caucasians.These results suggest that these two SNPs (rs2276466 and rs3136038) in ERCC4 may be functional and contribute to SCCHN susceptibility. However, our findings need to be replicated in further large epidemiological and functional studies.Item Open Access Association of Common Genetic Polymorphisms with Melanoma Patient IL-12p40 Blood Levels, Risk, and Outcomes.(J Invest Dermatol, 2015-09) Fang, Shenying; Wang, Yuling; Chun, Yun S; Liu, Huey; Ross, Merrick I; Gershenwald, Jeffrey E; Cormier, Janice N; Royal, Richard E; Lucci, Anthony; Schacherer, Christopher W; Reveille, John D; Chen, Wei; Sui, Dawen; Bassett, Roland L; Wang, Li-E; Wei, Qingyi; Amos, Christopher I; Lee, Jeffrey ERecent investigation has identified association of IL-12p40 blood levels with melanoma recurrence and patient survival. No studies have investigated associations of single-nucleotide polymorphisms (SNPs) with melanoma patient IL-12p40 blood levels or their potential contributions to melanoma susceptibility or patient outcome. In the current study, 818,237 SNPs were available for 1,804 melanoma cases and 1,026 controls. IL-12p40 blood levels were assessed among 573 cases (discovery), 249 cases (case validation), and 299 controls (control validation). SNPs were evaluated for association with log[IL-12p40] levels in the discovery data set and replicated in two validation data sets, and significant SNPs were assessed for association with melanoma susceptibility and patient outcomes. The most significant SNP associated with log[IL-12p40] was in the IL-12B gene region (rs6897260, combined P=9.26 × 10(-38)); this single variant explained 13.1% of variability in log[IL-12p40]. The most significant SNP in EBF1 was rs6895454 (combined P=2.24 × 10(-9)). A marker in IL12B was associated with melanoma susceptibility (rs3213119, multivariate P=0.0499; OR=1.50, 95% CI 1.00-2.24), whereas a marker in EBF1 was associated with melanoma-specific survival in advanced-stage patients (rs10515789, multivariate P=0.02; HR=1.93, 95% CI 1.11-3.35). Both EBF1 and IL12B strongly regulate IL-12p40 blood levels, and IL-12p40 polymorphisms may contribute to melanoma susceptibility and influence patient outcome.Item Open Access Correlation between base-excision repair gene polymorphisms and levels of in-vitro BPDE-induced DNA adducts in cultured peripheral blood lymphocytes.(PloS one, 2012-01) Yu, Hongping; Zhao, Hui; Wang, Li-E; Liu, Zhensheng; Li, Donghui; Wei, QingyiIn vitro benzo[a]pyrene diol epoxide (BPDE)-induced DNA adducts in cultured peripheral lymphocytes have been shown to be a phenotypic biomarker of individual's DNA repair phenotype that is associated with cancer risk. In this study, we explored associations between genotypes of base-excision repair genes (PARP1 Val762Ala, APEX1 Asp148Glu, and XRCC1 Arg399Gln) and in vitro BPDE-induced DNA adducts in cultured peripheral blood lymphocytes in 706 cancer-free non-Hispanic white subjects. We found that levels of BPDE-induced DNA adducts were significantly higher in ever smokers than in never smokers and that individuals with the Glu variant genotypes (i.e., Asp/Glu and Glu/Glu) exhibited lower levels of BPDE-induced DNA adducts than did individuals with the common Asp/Asp homozygous genotype (median RAL levels: 32.0 for Asp/Asp, 27.0 for Asp/Glu, and 17.0 for Glu/Glu, respectively; P(trend) = 0.030). Further stratified analysis showed that compared with individuals with the common APEX1-148 homozygous Asp/Asp genotype, individuals with the APEX1-148Asp/Glu genotype or the Glu/Glu genotype had a lower risk of having higher-level adducts (adjusted OR = 0.60, 95% CI: 0.36-0.98 and adjusted OR = 0.47, 95% CI: 0.26-0.86, respectively; P(trend) = 0.012) among smokers. Such an effect was not observed in non-smokers. However, there was no significant interaction between the APEX1 Asp148Glu polymorphism and smoking exposure in this study population (P = 0.512). Additional genotype-phenotype analysis found that the APEX1-148Glu allele had significantly increased expression of APEX1 mRNA in 270 Epstein-Barr virus-transformed lymphoblastoid cell lines, which is likely associated with more active repair activity. Our findings suggest that the functional APEX1-148Glu allele is associated with reduced risk of having high levels of BPDE-induced DNA adducts mediated with high levels of mRNA expression.Item Open Access ERCC1 and ERCC2 variants predict survival in gastric cancer patients.(PloS one, 2013-01) Li, Yangkai; Liu, Zhensheng; Liu, Hongliang; Wang, Li-E; Tan, Dongfeng; Ajani, Jaffer A; Wei, Qing-YiPURPOSE: ERCC1 and ERCC2 play critical roles in the nucleotide excision repair pathway that effectively repairs DNA damage induced by chemotherapeutic agents. Therefore, functional single nucleotide polymorphisms (SNPs) in these genes could have an impact on clinical outcomes in cancer patients who received chemotherapy. However, few studies have simultaneously investigated the roles of ERCC1 and ERCC2 SNPs in clinical outcomes in gastric cancer patients. EXPERIMENTAL DESIGN: We genotyped by the TaqMan assay three common, potentially functional ERCC1 (rs3212986) and ERCC2 SNPs (rs13181 and rs1799793) in 360 gastric cancer patients. We used both Kaplan-Meier tests and Cox proportional hazards models to evaluate the effects of ERCC1 and ERCC2 genotypes and haplotypes on clinical outcomes. RESULTS: We found that, compared with ERCC2 rs1799793 GG+AG genotypes, the homozygous variant AA genotype was associated with significantly poorer overall survival (OS) (AA vs. GG+AG, log-rank P=0.012) and significantly higher risk of death (AA vs. GG+AG, Adjusted hazards ratio [HR] 2.13; 95% CI, 1.28 to 3.56; P=0.004). In combined analyses, patients with any one of the three unfavorable genotypes (i.e. ERCC1 rs3212986 TT, ERCC2 rs13181 GG and rs1799793 AA) had statistically significant hazards of poor prognosis (Adjusted HR, 1.54; 95% CI, 1.06 to 2.25; P=0.025), compared with those without any unfavorable genotypes. Furthermore, the haplotype A-G-G (rs1799793/rs13181/rs3212986) had a significant impact on OS (Adjusted HR, 1.57; 95% CI, 1.11 to 2.21; P=0.011), compared with the common haplotype G-T-G. CONCLUSION: ERCC1 and ERCC2 functional SNPs may jointly affect OS in Caucasian gastric cancer patients. Additional large prospective studies are essential to confirm our findings.Item Open Access Genetic variants in fanconi anemia pathway genes BRCA2 and FANCA predict melanoma survival.(The Journal of investigative dermatology, 2015-02) Yin, Jieyun; Liu, Hongliang; Liu, Zhensheng; Wang, Li-E; Chen, Wei V; Zhu, Dakai; Amos, Christopher I; Fang, Shenying; Lee, Jeffrey E; Wei, QingyiCutaneous melanoma (CM) is the most lethal skin cancer. The Fanconi anemia (FA) pathway involved in DNA crosslink repair may affect CM susceptibility and prognosis. Using data derived from published genome-wide association study, we comprehensively analyzed the associations of 2,339 common single-nucleotide polymorphisms (SNPs) in 14 autosomal FA genes with overall survival (OS) in 858 CM patients. By performing false-positive report probability corrections and stepwise Cox proportional hazards regression analyses, we identified significant associations between CM OS and four putatively functional SNPs: BRCA2 rs10492396 (AG vs. GG: adjusted hazard ratio (adjHR)=1.85, 95% confidence interval (CI)=1.16-2.95, P=0.010), rs206118 (CC vs. TT+TC: adjHR=2.44, 95% CI=1.27-4.67, P=0.007), rs3752447 (CC vs. TT+TC: adjHR=2.10, 95% CI=1.38-3.18, P=0.0005), and FANCA rs62068372 (TT vs. CC+CT: adjHR=1.85, 95% CI=1.27-2.69, P=0.001). Moreover, patients with an increasing number of unfavorable genotypes (NUG) of these loci had markedly reduced OS and melanoma-specific survival (MSS). The final model incorporating with NUG, tumor stage, and Breslow thickness showed an improved discriminatory ability to classify both 5-year OS and 5-year MSS. Additional investigations, preferably prospective studies, are needed to validate our findings.Item Open Access Genetic variants of NOXA and MCL1 modify the risk of HPV16-associated squamous cell carcinoma of the head and neck.(BMC cancer, 2012-05) Zhou, Ziyuan; Sturgis, Erich M; Liu, Zhensheng; Wang, Li-E; Wei, Qingyi; Li, GuojunThe cooperation between phorbol 12-myristate 13-acetate induced protein 1 (NOXA) and myeloid cell leukemia 1 (MCL1) is critical in the intrinsic apoptotic pathway. Human papillomavirus 16 (HPV16), by inducing p53 and pRb-E2F degradation, may play an essential role in development of squamous cell carcinoma of the head and neck (SCCHN) through NOXA-MCL1 axis-mediated apoptosis. Therefore, genetic variants of NOXA and MCL1 may modify the SCCHN risk associated with HPV16 seropositivity.HPV16 serology was obtained by immunoadsorption assay. Four functional SNPs in the promoter of NOXA (rs9957673, rs4558496) and MCL1 (rs9803935, rs3738485) were genotyped for 380 cases and 335 frequency-matched cancer-free controls of non-Hispanic whites.Associations between the four polymorphisms and SCCHN risk were not significant, while we observed a significantly joint effect on SCCHN risk between the polymorphisms and HPV16 seropositivity. Notably, this effect modification was particularly pronounced for oropharyngeal cancer in subgroups including never smokers, never drinkers and younger subjects.Our results suggested that polymorphisms of NOXA and MCL1 may modify the risk of HPV16-associated oropharyngeal cancer. The further identification of population subgroups at higher risk provides evidence that HPV-targeting treatment may help benefit SCCHN. However, larger studies are needed to validate our findings.Item Open Access Genome-wide association study identifies a new melanoma susceptibility locus at 1q21.3.(Nature genetics, 2011-10-09) Macgregor, Stuart; Montgomery, Grant W; Liu, Jimmy Z; Zhao, Zhen Zhen; Henders, Anjali K; Stark, Mitchell; Schmid, Helen; Holland, Elizabeth A; Duffy, David L; Zhang, Mingfeng; Painter, Jodie N; Nyholt, Dale R; Maskiell, Judith A; Jetann, Jodie; Ferguson, Megan; Cust, Anne E; Jenkins, Mark A; Whiteman, David C; Olsson, Håkan; Puig, Susana; Bianchi-Scarrà, Giovanna; Hansson, Johan; Demenais, Florence; Landi, Maria Teresa; Dębniak, Tadeusz; Mackie, Rona; Azizi, Esther; Bressac-de Paillerets, Brigitte; Goldstein, Alisa M; Kanetsky, Peter A; Gruis, Nelleke A; Elder, David E; Newton-Bishop, Julia A; Bishop, D Timothy; Iles, Mark M; Helsing, Per; Amos, Christopher I; Wei, Qingyi; Wang, Li-E; Lee, Jeffrey E; Qureshi, Abrar A; Kefford, Richard F; Giles, Graham G; Armstrong, Bruce K; Aitken, Joanne F; Han, Jiali; Hopper, John L; Trent, Jeffrey M; Brown, Kevin M; Martin, Nicholas G; Mann, Graham J; Hayward, Nicholas KWe performed a genome-wide association study of melanoma in a discovery cohort of 2,168 Australian individuals with melanoma and 4,387 control individuals. In this discovery phase, we confirm several previously characterized melanoma-associated loci at MC1R, ASIP and MTAP-CDKN2A. We selected variants at nine loci for replication in three independent case-control studies (Europe: 2,804 subjects with melanoma, 7,618 control subjects; United States 1: 1,804 subjects with melanoma, 1,026 control subjects; United States 2: 585 subjects with melanoma, 6,500 control subjects). The combined meta-analysis of all case-control studies identified a new susceptibility locus at 1q21.3 (rs7412746, P = 9.0 × 10(-11), OR in combined replication cohorts of 0.89 (95% CI 0.85-0.95)). We also show evidence suggesting that melanoma associates with 1q42.12 (rs3219090, P = 9.3 × 10(-8)). The associated variants at the 1q21.3 locus span a region with ten genes, and plausible candidate genes for melanoma susceptibility include ARNT and SETDB1. Variants at the 1q21.3 locus do not seem to be associated with human pigmentation or measures of nevus density.Item Open Access Genome-wide gene-environment interaction analysis for asbestos exposure in lung cancer susceptibility.(Carcinogenesis, 2012-08) Wei, Sheng; Wang, Li-E; McHugh, Michelle K; Han, Younghun; Xiong, Momiao; Amos, Christopher I; Spitz, Margaret R; Wei, Qingyi WeiAsbestos exposure is a known risk factor for lung cancer. Although recent genome-wide association studies (GWASs) have identified some novel loci for lung cancer risk, few addressed genome-wide gene-environment interactions. To determine gene-asbestos interactions in lung cancer risk, we conducted genome-wide gene-environment interaction analyses at levels of single nucleotide polymorphisms (SNPs), genes and pathways, using our published Texas lung cancer GWAS dataset. This dataset included 317 498 SNPs from 1154 lung cancer cases and 1137 cancer-free controls. The initial SNP-level P-values for interactions between genetic variants and self-reported asbestos exposure were estimated by unconditional logistic regression models with adjustment for age, sex, smoking status and pack-years. The P-value for the most significant SNP rs13383928 was 2.17×10(-6), which did not reach the genome-wide statistical significance. Using a versatile gene-based test approach, we found that the top significant gene was C7orf54, located on 7q32.1 (P = 8.90×10(-5)). Interestingly, most of the other significant genes were located on 11q13. When we used an improved gene-set-enrichment analysis approach, we found that the Fas signaling pathway and the antigen processing and presentation pathway were most significant (nominal P < 0.001; false discovery rate < 0.05) among 250 pathways containing 17 572 genes. We believe that our analysis is a pilot study that first describes the gene-asbestos interaction in lung cancer risk at levels of SNPs, genes and pathways. Our findings suggest that immune function regulation-related pathways may be mechanistically involved in asbestos-associated lung cancer risk.Item Open Access Genotypes and haplotypes of the VEGF gene and survival in locally advanced non-small cell lung cancer patients treated with chemoradiotherapy.(BMC cancer, 2010-08-16) Guan, Xiaoxiang; Yin, Ming; Wei, Qingyi; Zhao, Hui; Liu, Zhensheng; Wang, Li-E; Yuan, Xianglin; O'Reilly, Michael S; Komaki, Ritsuko; Liao, ZhongxingVascular endothelial growth factor (VEGF) is a major mediator of angiogenesis involving in carcinogenesis, including lung cancer. We hypothesized that VEGF polymorphisms may affect survival outcomes among locally advanced non-small cell lung cancer (LA-NSCLC) patients.We genotyped three potentially functional VEGF variants [-460 T > C (rs833061), -634 G > C (rs2010963), and +936 C > T (rs3025039)] and estimated haplotypes in 124 Caucasian patients with LA-NSCLC treated with definitive radiotherapy. We used Kaplan-Meier log-rank tests, and Cox proportional hazard models to evaluate the association between VEGF variants and overall survival (OS).Gender, Karnofsky's performance scores (KPS) and clinical stage seemed to influence the OS. The variant C genotypes were independently associated with significantly improved OS (CT+CC vs. TT: adjusted hazard ratio [HR] = 0.58; 95% confidence interval [CI] = 0.37-0.92, P = 0.022), compared with the VEGF -460 TT genotype.Our study suggests that VEGF -460 C genotypes may be associated with a better survival of LA-NSCLC patients after chemoradiotherapy. Large studies are needed to confirm our findings.Item Open Access Polymorphisms at the microRNA binding-site of the stem cell marker gene CD133 modify susceptibility to and survival of gastric cancer.(Mol Carcinog, 2015-06) Wang, Qiming; Liu, Hongliang; Xiong, Huihua; Liu, Zhensheng; Wang, Li-E; Qian, Ji; Muddasani, Ramya; Lu, Victoria; Tan, Dongfeng; Ajani, Jaffer A; Wei, QingyiCD133 is one of the most common stem cell markers, and functional single nucleotide polymorphisms (SNPs) of CD133 may modulate its gene functions and thus cancer risk and patient survival. We hypothesized that potentially functional CD133 SNPs are associated with gastric cancer (GC) risk and survival. To test this hypothesis, we conducted a case-control study of 371 GC patients and 313 cancer-free controls frequency-matched by age, sex, and ethnicity. We genotyped four selected, potentially functional CD133 SNPs (rs2240688A>C, rs7686732C>G, rs10022537T>A, and rs3130C>T) and used logistic regression analysis for associations of these SNPs with GC risk and Cox hazards regression analysis for survival. We found that compared with the miRNA binding site rs2240688 AA genotype, AC + CC genotypes were associated with significantly increased GC risk (adjusted OR = 1.52, 95% CI = 1.09-2.13); for another miRNA binding site rs3130C>T SNP, the TT genotype was associated with significantly reduced GC risk (adjusted OR = 0.68, 95% CI = 0.48-0.97), compared with CC + CT genotypes. In all patients, the risk rs3130 TT variant genotype was significantly associated with overall survival (OS) (adjusted P(trend) = 0.016 and 0.007 under additive and recessive models, respectively). These findings suggest that these two CD133 miRNA binding site variants, rs2240688 and rs3130, may be potential biomarkers for genetic susceptibility to GC and possible predictors for survival in GC patients but require further validation by larger studies.Item Unknown Polymorphisms in the SULF1 gene are associated with early age of onset and survival of ovarian cancer.(Journal of experimental & clinical cancer research : CR, 2011-01-07) Han, Chan H; Huang, Yu-Jing; Lu, Karen H; Liu, Zhensheng; Mills, Gordon B; Wei, Qingyi; Wang, Li-ESULF1 (sulfatase 1) selectively removes the 6-O-sulphate group from heparan sulfate, changing the binding sites for extracellular growth factors. SULF1 expression has been reported to be decreased in various cancers, including ovarian cancer. We hypothesized that single nucleotide polymorphisms (SNPs) of SULF1 would impact clinicopathologic characteristics.We genotyped five common (minor allele frequency>0.05) regulatory SNPs with predicted functionalities (rs2623047 G>A, rs13264163 A>G, rs6990375 G>A, rs3802278 G>A, and rs3087714 C>T) in 168 patients with primary epithelial ovarian cancer, using the polymerase chain reaction-restriction fragment length polymorphism method.We found that rs2623047 G>A was significantly associated with an early age of onset of ovarian cancer in the G allele dose-response manner (P = 0.027; Ptrend = 0.007) and that rs2623047 GG/GA genotypes were associated with longer progression-free survival; rs6990375 G>A was also associated with the early age of onset in the A allele dose-response manner (P = 0.013; Ptrend= 0.009). The significant differences in age of disease onset persisted among carriers of haplotypes of rs2623047 and rs6990375 (P = 0.014; Ptrend = 0.004). In luciferase reporter gene assays, rs2623047 G allele showed a slightly higher promoter activity than the A allele in the SKOV3 tumorigenic cell line.These findings suggest that genetic variations in SULF1 may play a role in ovarian cancer onset and prognosis. Further studies with large sample sizes and of the mechanistic relevance of SULF1 SNPs are warranted.Item Unknown Polymorphisms of homologous recombination genes and clinical outcomes of non-small cell lung cancer patients treated with definitive radiotherapy.(PloS one, 2011-01) Yin, Ming; Liao, Zhongxing; Huang, Yu-Jing; Liu, Zhensheng; Yuan, Xianglin; Gomez, Daniel; Wang, Li-E; Wei, QingyiThe repair of DNA double-strand breaks (DSBs) is the major mechanism to maintain genomic stability in response to irradiation. We hypothesized that genetic polymorphisms in DSB repair genes may affect clinical outcomes among non-small cell lung cancer (NSCLC) patients treated with definitive radio(chemo)therapy. We genotyped six potentially functional single nucleotide polymorphisms (SNPs) (i.e., RAD51 -135G>C/rs1801320 and -172G>T/rs1801321, XRCC2 4234G>C/rs3218384 and R188H/rs3218536 G>A, XRCC3 T241M/rs861539 and NBN E185Q/rs1805794) and estimated their associations with overall survival (OS) and radiation pneumonitis (RP) in 228 NSCLC patients. We found a predictive role of RAD51 -135G>C SNP in RP development (adjusted hazard ratio [HR] = 0.52, 95% confidence interval [CI], 0.31-0.86, P = 0.010 for CG/CC vs. GG). We also found that RAD51 -135G>C and XRCC2 R188H SNPs were independent prognostic factors for overall survival (adjusted HR = 1.70, 95% CI, 1.14-2.62, P = 0.009 for CG/CC vs. GG; and adjusted HR = 1.70; 95% CI, 1.02-2.85, P = 0.043 for AG vs. GG, respectively) and that the SNP-survival association was most pronounced in the presence of RP. Our study suggests that HR genetic polymorphisms, particularly RAD51 -135G>C, may influence overall survival and radiation pneumonitis in NSCLC patients treated with definitive radio(chemo)therapy. Large studies are needed to confirm our findings.Item Unknown Polymorphisms of nucleotide excision repair genes predict melanoma survival.(The Journal of investigative dermatology, 2013-07) Li, Chunying; Yin, Ming; Wang, Li-E; Amos, Christopher I; Zhu, Dakai; Lee, Jeffrey E; Gershenwald, Jeffrey E; Grimm, Elizabeth A; Wei, QingyiMelanoma is the most highly malignant skin cancer, and nucleotide excision repair (NER) is involved in melanoma susceptibility. In this analysis of 1,042 melanoma patients, we evaluated whether genetic variants of NER genes may predict survival outcome of melanoma patients. We used genotyping data of 74 tagging single-nucleotide polymorphisms (tagSNPs) in eight core NER genes from our genome-wide association study (including two in XPA, 14 in XPC, three in XPE, four in ERCC1, 10 in ERCC2, eight in ERCC3, 14 in ERCC4, and 19 in ERCC5) and evaluated their associations with prognosis of melanoma patients. Using the Cox proportional hazards model and Kaplan-Meier analysis, we found a predictive role of XPE rs28720291, ERCC5 rs4150314, XPC rs2470458, and ERCC2 rs50871 SNPs in the prognosis of melanoma patients (rs28720291: AG vs. GG, adjusted hazard ratio (adjHR)=11.2, 95% confidence interval (CI) 3.04-40.9, P=0.0003; rs4150314: AG vs. GG, adjHR=4.76, 95% CI 1.09-20.8, P=0.038; rs2470458: AA vs. AG/GG, adjHR=2.11, 95% CI 1.03-4.33, P=0.040; and rs50871: AA vs. AC/CC adjHR=2.27, 95% CI 1.18-4.35, P=0.015). Patients with an increasing number of unfavorable genotypes had markedly increased death risk. Genetic variants of NER genes, particularly XPE rs28720291, ERCC5 rs4150314, XPC rs2470458, and ERCC2 rs50871, may independently or jointly modulate survival outcome of melanoma patients. Because our results were based on a median follow-up of 3 years without multiple test corrections, additional large prospective studies are needed to confirm our findings.Item Unknown The miR-184 binding-site rs8126 T>C polymorphism in TNFAIP2 is associated with risk of gastric cancer.(PloS one, 2013-01) Xu, Yu; Ma, Hongxia; Yu, Hongping; Liu, Zhensheng; Wang, Li-E; Tan, Dongfeng; Muddasani, Ramya; Lu, Victoria; Ajani, Jaffer A; Wang, Yanong; Wei, QingyiTNFAIP2 is a crucial gene involved in apoptosis. Single nucleotide polymorphisms (SNPs) in its miRNA binding sites could modulate functions of the miRNA-target genes and thus risk of cancers. In this study, we investigated associations between potentially functional SNPs in the miRNA binding sites of the 3'UTR of TNFAIP2 and gastric cancer risk in a US population.We conducted a case-control study of 301 gastric cancer patients and 313 cancer-free controls frequency-matched by age, sex and ethnicity. We genotyped four selected TNFAIP2 SNPs (rs8126 T>C, rs710100 G>A, rs1052912 G>A and rs1052823 G>T) and used the logistic regression analysis to assess associations of these SNPs with cancer risk.The rs8126 CC genotype was associated with a significantly elevated risk of gastric cancer (adjusted OR = 2.00, 95% CI = 1.09-3.64 and P = 0.024), compared with the combined rs8126 TT+TC genotypes, particularly in current drinkers. However, none of other TNFAIP2 SNPs was associated with risk of gastric cancer.Our data suggested that the TNFAIP2 miRNA binding site rs8126 T>C SNP may be a marker for susceptibility to gastric cancer, and this finding requires further validation by larger studies.Item Unknown The relationship between blood IL-12p40 level and melanoma progression.(Int J Cancer, 2015-04-15) Fang, Shenying; Wang, Yuling; Chun, Yun Shin; Liu, Huey; Ross, Merrick I; Gershenwald, Jeffrey E; Cormier, Janice N; Royal, Richard E; Lucci, Anthony; Schacherer, Christopher W; Reveille, John D; Sui, Dawen; Bassett, Roland L; Wang, Li-E; Wei, Qingyi; Amos, Christopher I; Lee, Jeffrey ECytokines such as Interleukin (IL)-12p70 ("IL-12") and IL-23 can influence tumor progression. We tested the hypothesis that blood levels of IL-12p40, the common subunit of both cytokines, are associated with melanoma progression. Blood from 2,048 white melanoma patients were collected at a single institution between March 1998 and March 2011. Plasma levels of IL-12p40 were determined for 573 patients (discovery), 249 patients (Validation 1) and 244 patients (Validation 2). Per 10-unit change of IL-12p40 level was used to investigate associations with melanoma patient outcome among all patients or among patients with early or advanced stage. Among stage I/II melanoma patients in the pooled data set, after adjustment for sex, age, stage and blood draw time from diagnosis, elevated IL-12p40 was associated with melanoma recurrence [hazard ratio (HR) = 1.04 per 10-unit increase in IL-12p40, 95% CI 1.02-1.06, p = 8.48 × 10(-5) ]; Elevated IL-12p40 was also associated with a poorer melanoma specific survival (HR = 1.06, 95% CI 1.03-1.09, p = 3.35 × 10(-5) ) and overall survival (HR = 1.05, 95% CI 1.03-1.08, p = 8.78×10(-7) ) in multivariate analysis. Among stage III/IV melanoma patients in the pooled data set, no significant association was detected between elevated IL-12p40 and overall survival, or with melanoma specific survival, with or without adjustment for the above covariates. Early stage melanoma patients with elevated IL-12p40 levels are more likely to develop disease recurrence and have a poorer survival. Further investigation with a larger sample size will be needed to determine the role of IL-12p40 in advanced stage melanoma patients.Item Unknown TNFRSF1B +676 T>G polymorphism predicts survival of non-small cell lung cancer patients treated with chemoradiotherapy.(BMC cancer, 2011-10-14) Guan, Xiaoxiang; Liao, Zhongxin; Ma, Hongxia; Qian, Ji; Liu, Zhensheng; Yuan, Xianglin; Gomez, Daniel; Komaki, Ritsuko; Wang, Li-E; Wei, QingyiThe dysregulation of gene expression in the TNF-TNFR superfamily has been involved in various human cancers including non-small cell lung cancer (NSCLC). Furthermore, functional polymorphisms in TNF-α and TNFRSF1B genes that alter gene expression are likely to be associated with risk and clinical outcomes of cancers. However, few reported studies have investigated the association between potentially functional SNPs in both TNF-α and TNFRSF1B and prognosis of NSCLC patients treated with chemoradiotherapy.We genotyped five potentially functional polymorphisms of TNF-α and TNFRSF1B genes [TNF-α -308 G>A (rs1800629) and -1031 T>C (rs1799964); TNFRSF1B +676 T>G (rs1061622), -1709A>T(rs652625) and +1663A>G (rs1061624)] in 225 NSCLC patients treated with chemoradiotherapy or radiotherapy alone. Kaplan-Meier survival analysis, log-rank tests and Cox proportional hazard models were used to evaluate associations between these variants and NSCLC overall survival (OS).We found that the TNFRSF1B +676 GG genotype was associated with a significantly better OS of NSCLC (GG vs. TT: adjusted HR = 0.38, 95% CI = 0.15-0.94; GG vs. GT/TT: adjusted HR = 0.35, 95% CI = 0.14-0.88). Further stepwise multivariate Cox regression analysis showed that the TNFRSF1B +676 GG was an independent prognosis predictor in this NSCLC cohort (GG vs. GT/TT: HR = 0.35, 95% CI = 0.14-0.85), in the presence of node status (N2-3 vs. N0-1: HR = 1.60, 95% CI = 1.09-2.35) and tumor stage (T3-4 vs. T0-2: HR = 1.48, 95% CI = 1.08-2.03).Although the exact biological function for this SNP remains to be explored, our findings suggest a possible role of TNFRSF1B +676 T>G (rs1061622) in the prognosis of NSCLC. Further large and functional studies are needed to confirm our findings.