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author:("Wu, xinfeng")
1.  Role of Select Genetic Variants in Lung Cancer Risk in African Americans 
Introduction
Black/white disparities in lung cancer incidence and mortality mandate an evaluation of underlying biological differences. We have previously shown higher risks of lung cancer associated with prior emphysema in African American compared with white lung cancer patients.
Methods
We therefore evaluated a panel of 1440 inflammatory gene variants in a two phase analysis (discovery and replication), added top GWAS lung cancer hits from Caucasian populations, and 28 SNPs from a published gene panel. The discovery set (477 self-designated African Americans cases, 366 controls matched on age, ethnicity, and gender) were from Houston, Texas. The external replication set (330 cases, 342 controls) was from the EXHALE study at Wayne State University.
Results
In discovery, 154 inflammation SNPs were significant (P<0.05) on univariate analysis, as was one of the gene panel SNPs (rs308738 in REV1, P=0.0013), and three GWAS hits, rs16969968 P=0.0014 and rs10519203 P=0.0003 in the 15q locus and rs2736100, the HTERT locus, P=0.0002. One inflammation SNP, rs950286, was successfully replicated with a concordant odds ratio of 1.46(1.14-1.87) in discovery, 1.37(1.05-1.77) in replication, and a combined OR of 1.40 (1.17-1.68). This SNP is intergenic between IRF4 and EXOC2 genes. We also constructed and validated epidemiologic and extended risk prediction models. The AUC for the epidemiologic discovery model was 0.77 and 0.80 for the extended model. For the combined datasets, the AUC values were 0.75 and 0.76, respectively.
Conclusion
As has been reported for other cancer sites and populations, incorporating top genetic hits into risk prediction models, provides little improvement in model performance and no clinical relevance.
doi:10.1097/JTO.0b013e318283da29
PMCID: PMC3623962  PMID: 23454887
2.  Energy Balance, Polymorphisms in the mTOR Pathway, and Renal Cell Carcinoma Risk 
Background
The interplay between obesity, physical activity, weight gain, and genetic variants in the mTOR pathway has not been studied in renal cell carcinoma (RCC). We examined the associations between obesity, weight gain, physical activity, and RCC risk. We also analyzed whether genetic variants in the mTOR pathway could modify the association.
Methods
Incident RCC case subjects and healthy control subjects were recruited from the University of Texas MD Anderson Cancer Center in Houston, Texas. Case subjects and control subjects were frequency matched. Epidemiologic data were collected by in-person interview. One hundred ninety single nucleotide polymorphisms (SNPs) from 22 genes in the mTOR pathway were extracted from previous genome-wide association studies. Logistic regression and regression spline were performed to obtain odds ratios (ORs). All statistical tests were two-sided.
Results
A total of 577 non-Hispanic white case subjects and 593 healthy control subjects were included. Obesity at age 20 years (OR = 1.92, 95% confidence interval [CI] = 1.05 to 3.50; P = .03) and age 40 years (OR = 2.03, 95% CI = 1.38 to 2.98; P < .001) and moderate (OR = 1.46, 95% CI = 1.02 to 2.09; P = .04) and massive weight gain (OR = 1.62, 95% CI = 1.10 to 2.39; P = .01) from age 20 to 40 years were each statistically significantly associated with increased RCC risk. Low physical activity was associated with a 4.08-fold increased risk. Among 190 SNPs in the mTOR pathway, six SNPs located in the AKT3 gene were statistically significantly associated with increased risk, and those with three or more unfavorable genotypes had a 1.72-fold increased risk of RCC.
Conclusion
Obesity, weight gain, physical activity, and genetic variants in the mTOR pathway may individually and jointly influence susceptibility to RCC.
doi:10.1093/jnci/djt005
PMCID: PMC3601952  PMID: 23378641
3.  Global assessment of genetic variation influencing response to retinoid chemoprevention in head and neck cancer patients 
Head and neck squamous cell carcinoma (HNSCC) patients are at an increased risk of developing a second primary tumor (SPT) or recurrence following curative treatment. 13-cis-retinoic acid (13-cRA) has been tested in chemoprevention clinical trials but the results have been inconclusive. We genotyped 9,465 SNPs in 450 patients from the Retinoid Head and Neck Second Primary Trial. SNPs were analyzed for associations with SPT/recurrence in patients receiving placebo to identify prognosis markers and further analyzed for effects of 13-cRA in patients with these prognostic loci. Thirteen loci identified a majority subgroup of patients at a high risk of SPT/recurrence and in whom 13-cRA was protective. Patients carrying the common genotype of rs3118570 in the retinoid X receptor (RXRA) were at a 3.33-fold increased risk (95% confidence interval [CI], 1.67–6.67) and represented over 70% of the study population. This locus also identified individuals who received benefit from chemoprevention with a 38% reduced risk (95% CI, 0.43–0.90). Analyses of cumulative effect and potential gene-gene interactions also implicated CDC25C:rs6596428 and JAK2:rs1887427 as two other genetic loci with major roles in prognosis and 13-cRA response. Patients with all three common genotypes had a 76% reduction in SPT/recurrence (95% CI, 0.093–0.64) following 13-cRA chemoprevention. Carriers of these common genotypes constituted a substantial percentage of the study population, indicating that a pharmacogenetics approach could help select patients for 13-cRA chemoprevention. The lack of any alternatives for reducing risk in these patients highlights the need for future clinical trials to prospectively validate our findings.
doi:10.1158/1940-6207.CAPR-10-0125
PMCID: PMC3955084  PMID: 21292633
HNSCC; SPT; single nucleotide polymorphisms; retinoids
4.  MicroRNA-Related Genetic Variants Associated with Clinical Outcomes in Early Stage Non-Small Cell Lung Cancer Patients 
Cancer research  2013;73(6):1867-1875.
Given the density of single nucleotide polymorphisms (SNPs) in the human genome and the sensitivity of single nucleotide changes in microRNA (miRNA) functionality and processing, we asked whether polymorphisms within miRNA processing pathways and binding sites may influence non-small cell lung cancer (NSCLC) patients’ prognosis. We genotyped 240 miRNA-related SNPs in 535 stage I and II NSCLC patients to determine associations with overall recurrence and survival, as well as effect in specific treatment subgroups. After correcting for multiple comparisons, the G allele of FZD4:rs713065 displayed a significant association with decreased risk of death in surgery-only patients (HR:0.46, 95%CI:0.32-0.65). DROSHA:rs6886834 variant A allele (HR:6.38, 95%CI:2.49-16.31) remained significant for increased risk of recurrence in the overall and surgery-only populations, respectively. FAS:rs2234978 G allele remained significantly associated with survival in all patients (HR:0.59, 95%CI:0.44-0.77), while borderline significant in subgroups (surgery only: HR:0.59, 95%CI:0.42-0.84; surgery plus chemo: HR:0.19, 95%CI:0.07-0.46). Luciferase assays demonstrated that the FAS SNP created a miR-651 functional binding site. Survival tree analysis was performed to classify patients into distinct risk subgroups based on their risk genotype combinations. These results indicate that miRNA-related polymorphisms may be associated with NSCLC patients’ clinical outcomes through altered miRNA regulation of target genes.
doi:10.1158/0008-5472.CAN-12-0873
PMCID: PMC3602350  PMID: 23378343
NSCLC; recurrence; overall survival; early stage; miRNA; binding site; single nucleotide polymorphism
5.  Sensation seeking genes and physical activity in youth 
Genes, brain, and behavior  2012;12(2):181-188.
Many studies examining genetic influences on physical activity (PA) have evaluated the impact of single nucleotide polymorphisms (SNPs) related to the development of lifestyle-related chronic diseases, under the hypothesis that they would be associated with PA. However, PA is a multi-determined behavior and associated with a multitude of health consequences. Thus, examining a broader range of candidate genes associated with a boarder range of PA correlates may provide new insights into the genetic underpinnings of PA. In this study we focus on one such correlate – sensation seeking behavior. Participants (N=1,130 Mexican origin youth) provided a saliva sample and data on PA and sensation seeking tendencies in 2008–09. Participants were genotyped for 630 functional and tagging variants in the dopamine, serotonin, and cannabinoid pathways. Overall 30% of participants (males – 37.6%; females – 22.0%) reported ≥60 minutes of PA on five out of seven days. After adjusting for gender, age and population stratification, and applying the Bayesian False Discovery Probability approach for assessing noteworthiness, four gene variants were significantly associated with PA. In a multivariable model, being male, having higher sensation seeking tendencies and at least one copy of the minor allele for SNPs in ACE (rs8066276 OR=1.44; p=0.012) and TPH2 (rs11615016 OR=1.73; p=0.021) were associated with increased likelihood of meeting PA recommendations. Participants with at least one copy of the minor allele for SNPs in SNAP25 (rs363035 OR=0.53; p=0.005) and CNR1 (rs6454672 OR=0.62; p=0.022) have decreased likelihood of meeting PA recommendations. Our findings extend current knowledge of the complex relationship between PA and possible genetic underpinnings.
doi:10.1111/gbb.12006
PMCID: PMC3581711  PMID: 23190435
Physical Activity; Genes; Sensation Seeking; Mexican origin youth
6.  Ionizing radiation-induced γ-H2AX activity in whole blood culture and the risk of lung cancer 
Background
Phenotypic biomarkers of DNA damage repair may enhance cancer risk prediction. The γ-H2AX formed at the sites of double strands break (DSB) after ionizing radiation (IR) is a specific marker of DNA damage.
Methods
In an ongoing case-control study, the baseline and IR-induced γ-H2AX levels in peripheral blood lymphocytes (PBLs) from frequency-matched 306 untreated lung cancer patients and 306 controls were measured by a laser scanning cytometer-based immunocytochemical method. The ratio of IR-induced γ-H2AX level to the baseline was used to evaluate inter-individual variation of DSB damage response and to assess the risk of lung cancer by using unconditional multivariable logistic regression with adjustment of age, sex, ethnicity, smoking status, family history of lung cancer, dust exposure and emphysema.
Results
The mean γ-H2AX ratio was significantly higher in cases than controls (1.46±0.14 vs. 1.41±0.12, P < 0.001). Dichotomized at the median in controls, high γ-H2AX ratio was significantly associated with increased risk of lung cancer (OR = 2.43, 95% CI: 1.66–3.56). There was also a significant dose-response relationship between γ-H2AX ratio and lung cancer risk in quartile analysis. Analysis of joint effects with other epidemiological risk factors revealed elevated risk with increasing number of risk factors.
Conclusion
γ-H2AX activity as shown by measuring DSB damage in IR-irradiated PBLs may be a novel phenotypic marker of lung cancer risk.
Impact
γ-H2AX assay is a robust and quantifiable image-based cytometer method that measures mutagen-induced DSB response in PBLs as a potential biomarker in lung cancer risk assessment.
doi:10.1158/1055-9965.EPI-12-0794
PMCID: PMC3601549  PMID: 23300022
Double strands break; γ-H2AX; mutagen sensitivity; lung cancer risk
7.  MicroRNA expression signatures during malignant progression from Barrett’s esophagus to esophageal adenocarcinoma 
Barrett’s esophagus (BE) is the precursor lesion of esophageal adenocarcinoma (EA), whose progression follows sequential stages. However, the low progression rate and the inadequacy and subjective interpretation of histological grading in predicting BE progression call for more objective biomarkers that can improve risk prediction. We performed a genome-wide profiling of 754 human microRNAs (miRNAs) in 35 normal epithelium (NE), 34 BE, and 36 EA tissues using Taqman real-time PCR-based profiling. Unsupervised hierarchical clustering using 294 modestly to highly expressed miRNAs showed clear clustering of two groups: NE versus BE/EA tissues. Moreover, there was an excellent clustering of Barrett’s metaplasia (BM, without dysplasia) tissues from NE tissues. However, BE tissues of different stages and EA tissues were interspersed. There were differentially expressed miRNAs at different stages. The majority of miRNA aberrations involved upregulation of expression in BE and EA tissues, with the most dramatic alterations occurring at the BM stage. Known oncomirs, such as miR-21, miR-25 and miR-223, and tumor suppressor miRNAs, including miR-205, miR-203, let-7c, and miR-133a, showed progressively altered expression from BE to EA. We also identified a number of novel miRNAs that showed progressively altered expression, including miR-301b, miR-618, and miR-23b. The significant miRNA alterations that were exclusive to EA but not BE included miR-375 downregulation and upregulation of five members of the miR-17-92 and its homologue clusters, which may become promising biomarkers for EA development.
doi:10.1158/1940-6207.CAPR-12-0276
PMCID: PMC3608471  PMID: 23466817
microRNA expression; Barrett’s esophagus; esophageal cancer
8.  Genome-Wide Catalogue of Chromosomal Aberrations in Barrett’s Esophagus and Esophageal Adenocarcinoma: a High-Density SNP Array Analysis 
To better understand the molecular mechanisms behind esophageal adenocarcinoma (EAC) tumorigenesis, we used high-density single nucleotide polymorphism (SNP) arrays to profile chromosomal aberrations at each of the four sequential progression stages – Barrett’s metaplasia (BM), low-grade dysplasia (LGD), high-grade dysplasia (HGD), and EAC, in 101 patients. We observed a significant trend toward increasing loss of chromosomes with higher progression stage. For BM, LGD, HGD, and EAC, respectively, the average numbers of chromosome arms with loss per sample were 0.30, 3.21, 7.70, and 11.90 (P for trend= 4.82 × 10−7), and the mean percentages of SNPs with allele loss were 0.1%, 1.8%, 6.6%, and 17.2% (P for trend = 2.64 × 10−6). In LGD, loss of 3p14.2 (68.4%) and 16q23.1 (47.4%) was limited to narrow regions within the FHIT (3p14.2) and WWOX (16q23.1) genes, whereas loss of 9p21 (68.4%) occurred in larger regions. A significant increase in the loss of other chromosomal regions was seen in HGD and EAC; loss of 17p (47.6%) was one of the most frequent events in EAC. Many recurrent small regions of chromosomal loss disrupted single genes, including FHIT, WWOX, RUNX1, KIF26B, MGC48628, PDE4D, C20orf133, GMDS, DMD, and PARK2, most of which are common fragile site (CFS) regions in the human genome. But RUNX1 at 21q22 appeared to be a potential tumor suppressor gene in EAC. Amplifications were less frequent than losses and mostly occurred in EAC. The 8q24 (containing Myc) and 8p23.1 (containing CTSB) were the two most frequently amplified regions. In addition, a significant trend toward increasing amplification was associated with higher progression stage.
doi:10.1158/1940-6207.CAPR-09-0265
PMCID: PMC3932797  PMID: 20651033
9.  Common variation at 2q22.3 (ZEB2) influences the risk of renal cancer 
Human Molecular Genetics  2012;22(4):825-831.
Genome-wide association studies (GWASs) of renal cell cancer (RCC) have identified four susceptibility loci thus far. To identify an additional RCC common susceptibility locus, we conducted a GWAS and performed a meta-analysis with published GWASs (totalling 2215 cases and 8566 controls of European background) and followed up the most significant association signals [nine single nucleotide polymorphisms (SNPs) in eight genomic regions] in 3739 cases and 8786 controls. A combined analysis identified a novel susceptibility locus mapping to 2q22.3 marked by rs12105918 (P = 1.80 × 10−8; odds ratio 1.29, 95% CI: 1.18–1.41). The signal localizes to intron 2 of the ZEB2 gene (zinc finger E box-binding homeobox 2). Our findings suggest that genetic variation in ZEB2 influences the risk of RCC. This finding provides further insights into the genetic and biological basis of inherited genetic susceptibility to RCC.
doi:10.1093/hmg/dds489
PMCID: PMC3554205  PMID: 23184150
10.  Variants in inflammation genes are implicated in risk of lung cancer in never smokers exposed to second-hand smoke 
Cancer discovery  2011;1(5):420-429.
Lung cancer in lifetime never smokers is distinct from that in smokers, but the role of separate or overlapping carcinogenic pathways has not been explored. We therefore evaluated a comprehensive panel of 11,737 SNPs in inflammatory-pathway genes in a discovery phase (451 lung cancer cases, 508 controls from Texas). SNPs that were significant were evaluated in a second external population (303 cases, 311 controls from the Mayo Clinic). An intronic SNP in the ACVR1B gene, rs12809597, was replicated with significance and restricted to those reporting adult exposure to environmental tobacco smoke Another promising candidate was a SNP in NR4A1, although the replication OR did not achieve statistical significance. ACVR1B belongs to the TGFR-β superfamily, contributing to resolution of inflammation and initiation of airway remodeling. An inflammatory microenvironment, (second hand smoking, asthma, or hay fever) is necessary for risk from these gene variants to be expressed. These findings require further replication, followed by targeted resequencing, and functional validation.
doi:10.1158/2159-8290.CD-11-0080
PMCID: PMC3919666  PMID: 22586632
lung cancer; never smokers; inflammation genes; sidestream exposure
11.  Fine-mapping of the 5p15.33, 6p22.1-p21.31 and 15q25.1 regions identifies functional and histology-specific lung cancer susceptibility loci in African-Americans 
Background
Genome-wide association studies of European and East Asian populations have identified lung cancer susceptibility loci on chromosomes 5p15.33, 6p22.1-p21.31 and 15q25.1. We investigated whether these regions contain lung cancer susceptibly loci in African-Americans refined previous association signals by utilizing the reduced linkage disequilibrium observed in African-Americans.
Methods
1308 African-American cases and 1241 African-American controls from three centers were genotyped for 760 single nucleotide polymorphisms spanning three regions, and additional SNP imputation was performed. Associations between polymorphisms and lung cancer risk were estimated using logistic regression, stratified by tumor histology where appropriate.
Results
The strongest associations were observed on 15q25.1 in/near CHRNA5, including a missense substitution (rs16969968: OR = 1.57, 95% CI = 1.25–1.97, P = 1.1 × 10−4) and variants in the 5′-UTR. Associations on 6p22.1-p21.31 were histology-specific and included a missense variant in BAT2 associated with squamous-cell carcinoma (rs2736158: OR = 0.64, 95% CI = 0.48–0.85, P = 1.82 × 10−3). Associations on 5p15.33 were detected near TERT, the strongest of which was rs2735940 (OR = 0.82, 95% CI = 0.73–0.93, P = 1.1 × 10−3). This association was stronger among cases with adenocarcinoma (OR = 0.75, 95% CI = 0.65–0.86, P = 8.1 × 10−5).
Conclusions
Polymorphisms in 5p15.33, 6p22.1-p21.31 and 15q25.1 are associated with lung cancer in African-Americans. Variants on 5p15.33 are stronger risk factors for adenocarcinoma and variants on 6p21.33 associated only with squamous-cell carcinoma.
Impact
Results implicate the BAT2, TERT and CHRNA5 genes in the pathogenesis of specific lung cancer histologies.
doi:10.1158/1055-9965.EPI-12-1007-T
PMCID: PMC3565099  PMID: 23221128
Lung cancer; adenocarcinoma; squamous-cell carcinoma; fine-mapping; African-American; genetic association
12.  Association of X-Ray Repair Cross-Complementing Group 1 Arg194Trp, Arg399Gln and Arg280His Polymorphisms with Head and Neck Cancer Susceptibility: A Meta-Analysis 
PLoS ONE  2014;9(1):e86798.
Background
Previous studies on the association of X-ray repair cross-complementing group 1 (XRCC1) Arg194Trp, Arg399Gln, and Arg280His polymorphisms with head and neck cancer (HNC) have produced inconsistent results. The aim of the present study was to evaluate the effects of these three polymorphic variants on HNC risk.
Methods
The PubMed and EMBASE databases were searched for genetic association studies on the XRCC1 Arg194Trp, Arg399Gln, and Arg280His polymorphisms and HNC risk. (The most recent search was conducted on 20 August, 2013.) Twenty-six studies were identified and meta-analysis was performed to evaluate the association between the polymorphism and HNC by calculating combined odds ratios and 95% confidence intervals.
Results
No significant association was found under the allelic, homozygous, heterozygote, and dominant genetic models in the overall comparison. Further, no significant association between the XRCC1 Arg399Gln and Arg280His polymorphisms and HNC risk was detected under the four genetic models in subgroup analyses based on ethnicity, cancer site, and whether or not the studies had been adjusted for cigarette smoking and alcohol. However, in stratified analyses based on cancer site, a significant association was found between the XRCC1 Arg194Trp polymorphism and oral cancer under the allelic, heterozygote, and dominant models. The XRCC1 Arg194Trp polymorphism was significantly associated with HNC risk in studies that were adjusted for smoking and alcohol under the homozygous and heterozygote models.
Conclusion
The meta-analysis results suggest that the XRCC1 Arg399Gln and Arg280His polymorphisms are probably not associated with the risk of HNC, but the XRCC1 Arg194Trp polymorphism was associated with increased risk of HNC in the subgroup analysis of studies adjusted for smoking and alcohol and with increased risk of oral cancer in the stratified analyses based on cancer site. Further studies with larger samples are needed to confirm these findings.
doi:10.1371/journal.pone.0086798
PMCID: PMC3907446  PMID: 24497981
13.  Application of Multi-SNP Approaches Bayesian LASSO and AUC-RF to Detect Main Effects of Inflammatory-Gene Variants Associated with Bladder Cancer Risk 
PLoS ONE  2013;8(12):e83745.
The relationship between inflammation and cancer is well established in several tumor types, including bladder cancer. We performed an association study between 886 inflammatory-gene variants and bladder cancer risk in 1,047 cases and 988 controls from the Spanish Bladder Cancer (SBC)/EPICURO Study. A preliminary exploration with the widely used univariate logistic regression approach did not identify any significant SNP after correcting for multiple testing. We further applied two more comprehensive methods to capture the complexity of bladder cancer genetic susceptibility: Bayesian Threshold LASSO (BTL), a regularized regression method, and AUC-Random Forest, a machine-learning algorithm. Both approaches explore the joint effect of markers. BTL analysis identified a signature of 37 SNPs in 34 genes showing an association with bladder cancer. AUC-RF detected an optimal predictive subset of 56 SNPs. 13 SNPs were identified by both methods in the total population. Using resources from the Texas Bladder Cancer study we were able to replicate 30% of the SNPs assessed. The associations between inflammatory SNPs and bladder cancer were reexamined among non-smokers to eliminate the effect of tobacco, one of the strongest and most prevalent environmental risk factor for this tumor. A 9 SNP-signature was detected by BTL. Here we report, for the first time, a set of SNP in inflammatory genes jointly associated with bladder cancer risk. These results highlight the importance of the complex structure of genetic susceptibility associated with cancer risk.
doi:10.1371/journal.pone.0083745
PMCID: PMC3877090  PMID: 24391818
14.  Identification of polymorphisms in ultraconserved elements associated with clinical outcomes in locally advanced colorectal adenocarcinoma 
Cancer  2012;118(24):6188-6198.
Background
Ultraconserved elements (UCEs) are non-coding genomic sequences completely identical among human, mouse, and rat species and harbor critical biological functions. We hypothesized that single nucleotide polymorphisms (SNPs) within UCEs are associated with clinical outcomes in colorectal cancer (CRC) patients.
Patients and Methods
Forty-eight SNPs within UCEs were genotyped in 662 patients with stage I–III CRC. The associations between genotypes and recurrence and survival were analyzed in stage II or III patients receiving fluoropyrimidine-based adjuvant chemotherapy using a training and validation design. The training set contained 115 stage II and 170 stage III patients, and the validation set contained 88 stage II and 112 stage III patients, respectively.
Results
Eight SNPs were associated with clinical outcomes stratified by disease stage. In particular, for stage II patients with at least one variant allele of rs7849, consistent association with increased recurrence risk was observed in the training set (HR: 2.39; 95%CI: 1.04–5.52), replication set (HR: 3.70; 95%CI: 1.42–9.64), and meta-analysis (HR: 2.89; 95%CI: 1.54–5.41). There were several other SNPs that were significant in training set, but not in the validation set. These include: rs2421099, rs16983007 and rs10211390 with recurrence, and rs6590611 with survival in stage II patients; and SNPs rs6124509 and rs11195893 with recurrence in stage III patients. In addition, we also observed significant cumulative effect of multiple risk genotypes and potential gene-gene interactions on recurrence risk.
Conclusions
This is the first study to evaluate the association between SNPs within UCEs and clinical outcome in CRC patients. Our results suggest that SNPs within UCEs may be valuable prognostic biomarkers for locally advanced CRC patients receiving 5FU-based chemotherapy.
doi:10.1002/cncr.27653
PMCID: PMC3465518  PMID: 22673945
SNP; ultraconserved elements; colorectal cancer; recurrence
15.  Meta-analysis identifies four new loci associated with testicular germ cell tumor 
Nature genetics  2013;45(6):10.1038/ng.2634.
We conducted a meta-analysis to identify new loci for testicular germ cell tumor (TGCT) susceptibility. In the discovery phase, 931 affected individuals and 1,975 controls from three genome wide association studies (GWAS) were analyzed. Replication was conducted in six independent sample sets totaling 3,211 affected individuals and 7,591 controls. In the combined analysis, TGCT risk was significantly associated with markers at four novel loci: 4q22.2 in HPGDS (per allele odds ratio (OR) 1.19, 95%CI 1.12–1.26, P = 1.11×10−8); 7p22.3 in MAD1L1 (OR 1.21, 95%CI 1.14–1.29, P = 5.59×10−9); 16q22.3 in RFWD3 (OR 1.26, 95%CI 1.18–1.34, P = 5.15×10−12); and 17q22 (rs9905704; OR 1.27, 95%CI 1.18–1.33; P = 4.32×10−13, and rs7221274; OR 1.20, 95%CI 1.12–1.28 P = 4.04×10−9), a locus which includes TEX14, RAD51C and PPM1E. The new TGCT susceptibility loci contain biologically plausible genes encoding proteins important for male germ cell development, chromosomal segregation and DNA damage response.
doi:10.1038/ng.2634
PMCID: PMC3723930  PMID: 23666239
16.  A LIN28B polymorphism predicts for colon cancer survival 
Cancer Biology & Therapy  2012;13(14):1390-1395.
The pathogenesis of sporadic colorectal cancer involves distinct pathways, with characteristic genomic alterations. The first pathway, chromosome instability (CIN), is driven by APC mutations and is typified by Kras mutations, p53 mutation/loss of heterozygosity, and deletions at chromosome 18q. The second pathway is referred to as microsatellite instability (MSI), a genetic hallmark of the accumulated mutations that occur as a consequence of derangements in the mismatch repair genes. Finally, proximal colon cancers may involve methylation of a number of genes, which is frequently referred to as the CpG island methylator phenotype (CIMP), and are associated with B-raf mutations. The ability to stratify colorectal cancers by risk would be facilitated by the identification of polymorphisms that might be utilized as biomarkers. LIN28B is an RNA binding protein that is overexpressed in colon cancers. We find that LIN28B rs314277 is associated with significant recurrence of colorectal cancer in Stage II disease, which may have translational therapeutic implications.
doi:10.4161/cbt.22336
PMCID: PMC3542229  PMID: 23052130
Colon cancer; LIN28B; SNP; prognosis; molecular pathogenesis; genetics; genomics
17.  Association of Aurora-A (STK15) Kinase Polymorphisms With Clinical Outcome of Esophageal Cancer Treated With Preoperative Chemoradiation 
Cancer  2011;118(17):10.1002/cncr.26581.
BACKGROUND:
Aurora-A/STK15 is a serine/threonine kinase critical for regulated chromosome segregation and cytokinesis. We investigated the association between 2 nonsynonymous single nucleotide polymorphisms in the coding region of STK15, T91A (Phe31Ile) and G169A (Val57Ile), and clinical outcome of esophageal cancer treated with preoperative chemoradiation.
METHODS:
Genotypes at Phe31Ile and Val57Ile were assessed from peripheral blood lymphocytes of 190 esophageal cancer patients and were correlated to response to treatment, recurrence rate, risk of death, disease-free survival (DFS) and median survival time (MTS).
RESULTS:
All patients had resectable esophageal or gastroesophageal junction cancer and received preoperative chemoradiation followed by esophagectomy. The heterozygous variant Phe31/Ile variant was significantly associated with tumor recurrence (odds ratio [OR] = 4.39; 95% confidence interval [CI], 2.12-8.94; P < .001), shorter DFS (P = .0001), and shorter MTS (P = .012). For patients receiving cisplatin-based therapy, only the variant Phe31/Ile had an adverse effect on response (OR = 2.8; 95% CI, 1.01-5.17; P = .048) and MTS (P = .026). The variant 91A-169G haplotype carried a significant risk for lack of complete response (OR = 2.54; 95% CI, 1.15-5.54) and higher rate of recurrence (OR = 2.73; 95%CI, 1.00-7.29). The presence of at least 1 variant allele at each locus further increased the risk of recurrence (adjusted OR = 6.21; 95% CI, 2.28-17.11; P = <.001), and was associated significantly shorter DFS (P = .003).
CONCLUSIONS:
Our study shows that functional SNPs in the STK15 gene are associated with higher rate of recurrence, higher likelihood of chemoratiotherapy-resistance, shorter DFS, and shorter MTS. Confirmation of our data and understanding the mechanisms through which STK15 functional SNPs mediate resistance to chemoradiotherapy are warranted.
doi:10.1002/cncr.26581
PMCID: PMC3831524  PMID: 22213102
Aurora-A; polymorphism; chemoradiotherapy; esophageal cancer; outcome
18.  Germline Prognostic Markers for Urinary Bladder Cancer: Obstacles and Opportunities 
Urologic oncology  2012;30(4):10.1016/j.urolonc.2012.04.003.
Urinary bladder cancer is a heterogeneous disease with diverse genetic and environmental risk factors that can influence disease risk or clinical course for recurrence, progression, and survival. Therefore, identification of these factors is paramount for disease prevention and optimal clinical management of bladder cancer patients. Of particular interest is the need to identify molecular biomarkers that can give accurate assessment of tumor biological potential and to predict treatment response. Recent advances in molecular biology, cytogenetic and genomic research have spurred discovery efforts for novel genetic, epigenetic, and proteomic biomarkers that are prognostic for cancer. This review focuses on some of the important germline polymorphisms found to be correlated with clinical outcomes in bladder cancer. So far the majority of the identified candidate loci was based on prior knowledge of pathogenesis and had not been validated for clinical applications. The future challenges are to analyze the wealth of information from whole-genome studies, to understand the underlying biological mechanisms of these associations, the network of gene-gene and gene-environment interactions, and to apply these markers for the identification of high-risk population for targeted, personalized therapy.
doi:10.1016/j.urolonc.2012.04.003
PMCID: PMC3824379  PMID: 22742565
Polymorphisms; prognostic markers; clinical outcome; bladder cancer
19.  KDM2A promotes lung tumorigenesis by epigenetically enhancing ERK1/2 signaling 
The Journal of Clinical Investigation  2013;123(12):5231-5246.
Epigenetic dysregulation has emerged as a major contributor to tumorigenesis. Histone methylation is a well-established mechanism of epigenetic regulation that is dynamically modulated by histone methyltransferases and demethylases. The pathogenic role of histone methylation modifiers in non–small cell lung cancer (NSCLC), which is the leading cause of cancer deaths worldwide, remains largely unknown. Here, we found that the histone H3 lysine 36 (H3K36) demethylase KDM2A (also called FBXL11 and JHDM1A) is frequently overexpressed in NSCLC tumors and cell lines. KDM2A and its catalytic activity were required for in vitro proliferation and invasion of KDM2A-overexpressing NSCLC cells. KDM2A overexpression in NSCLC cells with low KDM2A levels increased cell proliferation and invasiveness. KDM2A knockdown abrogated tumor growth and invasive abilities of NSCLC cells in mouse xenograft models. We identified dual-specificity phosphatase 3 (DUSP3) as a key KDM2A target gene and found that DUSP3 dephosphorylates ERK1/2 in NSCLC cells. KDM2A activated ERK1/2 through epigenetic repression of DUSP3 expression via demethylation of dimethylated H3K36 at the DUSP3 locus. High KDM2A levels correlated with poor prognosis in NSCLC patients. These findings uncover an unexpected role for a histone methylation modifier in activating ERK1/2 in lung tumorigenesis and metastasis, suggesting that KDM2A may be a promising therapeutic target in NSCLC.
doi:10.1172/JCI68642
PMCID: PMC3859406  PMID: 24200691
20.  A Genetic Polymorphism in pre-miR-27a Confers Clinical Outcome of Non-Small Cell Lung Cancer in a Chinese Population 
PLoS ONE  2013;8(11):e79135.
Background
Recent evidence indicates that microRNAs (miRNAs) can function as tumor suppressors and oncogenes. Single nucleotide polymorphisms (SNPs) at miRNA genes can influence the maturation of miRNAs or miRNA-mediated transcriptional regulation. Our objective was to investigate the association of SNPs in deregulated miRNAs with clinical outcome in patients with non-small cell lung cancer (NSCLC) in a Chinese population.
Methods
Deregulated miRNAs in NSCLC and their SNPs were identified through public databases. A single SNP, rs895819 in pre-miR-27a, was found suitable for selection. TaqMan assays were performed for genotyping and to assess the effect on the overall survival (OS) and chemotherapy response in 576 NSCLC patients.
Results
Log-rank test and Cox regression analysis indicated that the G allele of rs895819 was associated with shorter survival and increased risk of death in NSCLC [dominant model: 22.0 vs. 46.0 months, P<0.001; adjusted hazard ratio (HR) = 1.71, 95% confidential interval (CI): 1.12–2.26]. Further stepwise regression analysis suggested that this SNP was an independently unfavorable factor for the prognosis of NSCLC and the effect remained significant in subgroup analysis stratified by clinical parameters and treatment status. Moreover, multivariate logistic regression analysis showed that the subjects with AG/GG genotypes of rs895819 had significantly decreased response rate to platinum-based chemotherapy compared to those with the AA genotype.
Conclusion
Our results suggest that the pre-miR-27a rs895819 polymorphism may influence NSCLC patients’ clinical outcome. Further large sample studies should be used to validate our findings.
doi:10.1371/journal.pone.0079135
PMCID: PMC3819265  PMID: 24223174
21.  Hepatocellular Carcinoma Risk Prediction Model for the General Population: The Predictive Power of Transaminases 
Background
Risk prediction models for hepatocellular carcinoma are available for individuals with chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections who are at high risk but not for the general population with average or unknown risk. We developed five simple risk prediction models based on clinically available data from the general population.
Methods
A prospective cohort of 428 584 subjects from a private health screening firm in Taiwan was divided into two subgroups—one with known HCV test results (n = 130 533 subjects) and the other without (n = 298 051 subjects). A total of 1668 incident hepatocellular carcinomas occurred during an average follow-up of 8.5 years. Model inputs included age, sex, health history–related variables; HBV or HCV infection–related variables; serum levels of alanine transaminase (ALT), aspartate transaminase (AST), and alfa-fetoprotein (AFP), as well as other variables of routine blood panels for liver function. Cox proportional hazards regression method was used to identify risk predictors of hepatocellular carcinoma. Receiver operating characteristic curves were used to assess discriminatory accuracy of the models. Models were internally validated. All statistical tests were two-sided.
Results
Age, sex, health history, HBV and HCV status, and serum ALT, AST, AFP levels were statistically significant independent predictors of hepatocellular carcinoma risk (all P < .05). Use of serum transaminases only in a model showed a higher discrimination compared with HBV or HCV only (for transaminases, area under the curve [AUC] = 0.912, 95% confidence interval [CI] = 0.909 to 0.915; for HBV, AUC = 0.840, 95% CI = 0.833 to 0.848; and for HCV, AUC = 0.841, 95% CI = 0.834 to 0.847). Adding HBV and HCV data to the transaminase-only model improved the discrimination (AUC = 0.933, 95% CI = 0.929 to 0.949). Internal validation showed high discriminatory accuracy and calibration of these models.
Conclusion
Models with transaminase data were best able to predict hepatocellular carcinoma risk even among subjects with unknown or HBV- or HCV-negative infection status.
doi:10.1093/jnci/djs372
PMCID: PMC3692381  PMID: 23073549
22.  Insulin-Like Growth Factor Binding Protein-2 Level Is Increased in Blood of Lung Cancer Patients and Associated with Poor Survival 
PLoS ONE  2013;8(9):e74973.
Background
We recently showed that IGFBP2 is overexpressed in primary lung cancer tissues. This study aims to determine whether IGFBP2 is elevated in blood samples of lung cancer patients and whether its level is associated with clinical outcomes.
Methodology/Principal Findings
Plasma IGFBP2 levels were determined blindly by enzyme-linked immunosorbent assay in 80 lung cancer patients and 80 case-matched healthy controls for comparison. We analyzed blood samples for IGFBP2 levels from an additional 84 patients with lung cancer and then tested for associations between blood IGFBP2 levels and clinical parameters in all 164 lung cancer patients. All statistical tests were two-sided and differences with p<0.05 were considered significant. The mean plasma concentration of IGFBP2 in lung cancer patients was significantly higher than that in healthy controls (388.12±261.00 ng/ml vs 219.30±172.84 ng/ml, p<0.001). IGFBP2 was increased in all types of lung cancer, including adenocarcinoma, squamous cell cancer, and small-cell cancer, regardless of patients’ age, sex, or smoking status. IGFBP2 levels were mildly but significantly associated with tumor size and were significantly higher in stage IV than stage I or III disease. A multivariate analysis showed that lung cancer patients whose blood IGFBP2 was higher than 160.9 ng/ml had a poor survival outcome, with a hazard ratio of 8.76 (95% CI 1.12-68.34, p=0.038 after adjustment for tumor size, pathology, and stage). The median survival time for patients with blood IGFBP2 >160.9 ng/ml is 15.1 months; whereas median survival time was 128.2 months for the patients whose blood IGFBP2 was ≤160.9 ng/ml (p =0.0002).
Conclusions/Significance
Blood IGFBP2 is significantly increased in lung cancer patients. A high circulating level of IGFBP2 is significantly associated with poor survival, suggesting that blood IGFBP2 levels could be a prognostic biomarker for lung cancer.
doi:10.1371/journal.pone.0074973
PMCID: PMC3775736  PMID: 24069370
23.  Systematic evaluation of apoptotic pathway gene polymorphisms and lung cancer risk 
Carcinogenesis  2012;33(9):1699-1706.
We adopted a two-stage study design to screen 927 single nucleotide polymorphisms (SNPs) located in 73 apoptotic-pathway genes in a case-control study and then performed a fast-track validation of the significant SNPs in a replication population to identify sequence variations in the apoptotic pathway modulating lung cancer risk. Fifty-five SNPs showed significant associations in the discovery population comprised of 661 lung cancer cases and 959 controls. Six of these SNPs located in three genes (Bcl-2, CASP9 and ANKS1B) were validated in a replication population with 1154 cases and 1373 controls. Additive model was the best-fitting model for five SNPs (rs1462129 and rs255102 of Bcl-2, rs6685648 of CASP9 and rs1549102, rs11110099 of ANKS1B) and recessive model was the best fit for one SNP (rs10745877 of ANKS1B). In the analysis of joint effects with subjects carrying no unfavorable genotypes as the reference group, those carrying one, two, and three or more unfavorable genotypes had an odds ratio (OR) of 2.22 [95% confidence interval (CI) = 1.08–4.57, P = 0.03], 2.70 (95% CI = 1.33–5.49; P = 0.006) and 4.13 (95% CI = 2.00–8.57; P = 0.0001), respectively (P for trend = 6.05E-06). The joint effect of unfavorable genotypes was also validated in the replication population. The SNPs identified are located in or near key genes known to play important roles in apoptosis regulation, supporting the strong biological relevance of our findings. Future studies are needed to identify the causal SNPs and elucidate the underlying molecular mechanisms.
doi:10.1093/carcin/bgs192
PMCID: PMC3514904  PMID: 22665367
24.  Hepatic stem cells and transforming growth factor β in hepatocellular carcinoma 
Hepatocellular carcinoma (HCC) is one of the most common and lethal cancers worldwide. It arises from modulation of multiple genes by mutations, epigenetic regulation, noncoding RNAs and translational modifications of encoded proteins. Although >40% of HCCs are clonal and thought to arise from cancer stem cells (CSCs), the precise identification and mechanisms of CSC formation remain poorly understood. A functional role of transforming growth factor (TGF)-β signalling in liver and intestinal stem cell niches has been demonstrated through mouse genetics. These studies demonstrate that loss of TGF-β signalling yields a phenotype similar to a human CSC disorder, Beckwith–Wiedemann syndrome. Insights into this powerful pathway will be vital for developing new therapeutics in cancer. Current clinical approaches are aimed at establishing novel cancer drugs that target activated pathways when the TGF-β tumour suppressor pathway is lost, and TGF-β itself could potentially be targeted in metastases. Studies delineating key functional pathways in HCC and CSC formation could be important in preventing this disease and could lead to simple treatment strategies; for example, use of vitamin D might be effective when the TGF-β pathway is lost or when wnt signalling is activated.
doi:10.1038/nrgastro.2012.114
PMCID: PMC3745216  PMID: 22710573
25.  The D2 Dopamine Receptor Gene and Nicotine Dependence Among Bladder Cancer Patients and Controls 
Behavior genetics  2009;40(1):49-58.
Multiple twin, family, and genetic studies have rendered substantial evidence supporting an association between hereditary factors and smoking initiation and maintenance. To investigate further the relationships between the DRD2 genotypes, cigarette use and nicotine dependence, we examined the prevalence of polymorphisms in the TaqIA (A1 and A2) and the TaqIB (B1 and B2) alleles among a series of 608 non-Hispanic White bladder cancer patients and 608 matched controls. Among ever-smoking controls, A1 and B1 genotypes exhibited a greater smoking intensity and were significantly younger at the age of initiation than A2A2 or B2B2 genotypes (two-sided P < 0.05). Among former smoking cases, persons with the A1 genotypes exhibited significantly higher mean pack-years and years of smoking, and were younger at the age of initiation than were persons with the A2A2 genotype (two-sided P < 0.05). Additionally, current smokers with the A1 genotypes reported fewer quit attempts than those with the A2A2 genotype (two-sided P < 0.01). The present study suggests that the DRD2 alleles A1 and B1 confer greater vulnerability to tobacco use.
doi:10.1007/s10519-009-9301-0
PMCID: PMC3719969  PMID: 19842028
DRD2; Bladder cancer; Nicotine dependence

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