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1.  A genome-wide association study of marginal zone lymphoma shows association to the HLA region 
Vijai, Joseph | Wang, Zhaoming | Berndt, Sonja I. | Skibola, Christine F. | Slager, Susan L. | de Sanjose, Silvia | Melbye, Mads | Glimelius, Bengt | Bracci, Paige M. | Conde, Lucia | Birmann, Brenda M. | Wang, Sophia S. | Brooks-Wilson, Angela R. | Lan, Qing | de Bakker, Paul I. W. | Vermeulen, Roel C. H. | Portlock, Carol | Ansell, Stephen M. | Link, Brian K. | Riby, Jacques | North, Kari E. | Gu, Jian | Hjalgrim, Henrik | Cozen, Wendy | Becker, Nikolaus | Teras, Lauren R. | Spinelli, John J. | Turner, Jenny | Zhang, Yawei | Purdue, Mark P. | Giles, Graham G. | Kelly, Rachel S. | Zeleniuch-Jacquotte, Anne | Ennas, Maria Grazia | Monnereau, Alain | Bertrand, Kimberly A. | Albanes, Demetrius | Lightfoot, Tracy | Yeager, Meredith | Chung, Charles C. | Burdett, Laurie | Hutchinson, Amy | Lawrence, Charles | Montalvan, Rebecca | Liang, Liming | Huang, Jinyan | Ma, Baoshan | Villano, Danylo J. | Maria, Ann | Corines, Marina | Thomas, Tinu | Novak, Anne J. | Dogan, Ahmet | Liebow, Mark | Thompson, Carrie A. | Witzig, Thomas E. | Habermann, Thomas M. | Weiner, George J. | Smith, Martyn T. | Holly, Elizabeth A. | Jackson, Rebecca D. | Tinker, Lesley F. | Ye, Yuanqing | Adami, Hans-Olov | Smedby, Karin E. | De Roos, Anneclaire J. | Hartge, Patricia | Morton, Lindsay M. | Severson, Richard K. | Benavente, Yolanda | Boffetta, Paolo | Brennan, Paul | Foretova, Lenka | Maynadie, Marc | McKay, James | Staines, Anthony | Diver, W. Ryan | Vajdic, Claire M. | Armstrong, Bruce K. | Kricker, Anne | Zheng, Tongzhang | Holford, Theodore R. | Severi, Gianluca | Vineis, Paolo | Ferri, Giovanni M. | Ricco, Rosalia | Miligi, Lucia | Clavel, Jacqueline | Giovannucci, Edward | Kraft, Peter | Virtamo, Jarmo | Smith, Alex | Kane, Eleanor | Roman, Eve | Chiu, Brian C. H. | Fraumeni, Joseph F. | Wu, Xifeng | Cerhan, James R. | Offit, Kenneth | Chanock, Stephen J. | Rothman, Nathaniel | Nieters, Alexandra
Nature Communications  2015;6:5751.
Marginal zone lymphoma (MZL) is the third most common subtype of B-cell non-Hodgkin lymphoma. Here we perform a two-stage GWAS of 1,281 MZL cases and 7,127 controls of European ancestry and identify two independent loci near BTNL2 (rs9461741, P=3.95 × 10−15) and HLA-B (rs2922994, P=2.43 × 10−9) in the HLA region significantly associated with MZL risk. This is the first evidence that genetic variation in the major histocompatibility complex influences MZL susceptibility.
Marginal zone lymphoma (MZL) is a common subtype of B-cell non-Hodgkin lymphoma. Here the authors carry out a two-stage genome-wide association study in over 8,000 Europeans and identify two new MZL risk loci at chromosome 6p, implicating the major histocompatibility complex in the disease for the first time.
doi:10.1038/ncomms6751
PMCID: PMC4287989  PMID: 25569183
2.  A genome-wide association study of renal cell carcinoma among African Americans 
Genome-wide association studies (GWAS) of renal cell carcinoma (RCC) in populations of European ancestry have identified four susceptibility loci. No GWAS has been conducted among African Americans (AAs), who experience a higher incidence of RCC. We conducted a GWAS in which we analyzed 1,136,723 common single-nucleotide polymorphisms (SNPs) among 255 cases and 375 controls of African ancestry, and further investigated 16 SNPs in a replication set (140 cases, 543 controls). The 12p11.23 variant rs10771279, located 77kb from the European-ancestry RCC marker rs718314, was associated with RCC risk in the GWAS (P=1.2 × 10−7) but did not replicate (P=0.99). Consistent with European-ancestry findings, the A allele of rs7105934 on 11q13.3 was associated with decreased risk [odds ratio (OR)=0.76, 95% confidence interval (CI)=0.64–0.91; P=0.0022]. The frequency of this allele was higher than that observed in the European-ancestry GWAS (0.56 and 0.07 respectively among controls). The rs7105934 association was stronger for clear cell RCC (ccRCC: OR=0.56; P=7.4 × 10−7) and absent for cases of other or unknown histology (OR=1.02; P=0.86). Analyses of rs7105934 by subtype among European-ancestry participants from these studies yielded similar findings (ORs 0.69 and 0.92 respectively). This study provides, to our knowledge, the first evidence that rs7105934 is an RCC susceptibility locus among AAs. Our finding that the association with this SNP may be specific to ccRCC is novel and requires additional investigation. Additional investigation of rs10771279 and other suggestive GWAS findings is also needed.
doi:10.1158/1055-9965.EPI-13-0818
PMCID: PMC3901793  PMID: 24220910
3.  Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer 
Wang, Yufei | McKay, James D. | Rafnar, Thorunn | Wang, Zhaoming | Timofeeva, Maria | Broderick, Peter | Zong, Xuchen | Laplana, Marina | Wei, Yongyue | Han, Younghun | Lloyd, Amy | Delahaye-Sourdeix, Manon | Chubb, Daniel | Gaborieau, Valerie | Wheeler, William | Chatterjee, Nilanjan | Thorleifsson, Gudmar | Sulem, Patrick | Liu, Geoffrey | Kaaks, Rudolf | Henrion, Marc | Kinnersley, Ben | Vallée, Maxime | LeCalvez-Kelm, Florence | Stevens, Victoria L. | Gapstur, Susan M. | Chen, Wei V. | Zaridze, David | Szeszenia-Dabrowska, Neonilia | Lissowska, Jolanta | Rudnai, Peter | Fabianova, Eleonora | Mates, Dana | Bencko, Vladimir | Foretova, Lenka | Janout, Vladimir | Krokan, Hans E. | Gabrielsen, Maiken Elvestad | Skorpen, Frank | Vatten, Lars | Njølstad, Inger | Chen, Chu | Goodman, Gary | Benhamou, Simone | Vooder, Tonu | Valk, Kristjan | Nelis, Mari | Metspalu, Andres | Lener, Marcin | Lubiński, Jan | Johansson, Mattias | Vineis, Paolo | Agudo, Antonio | Clavel-Chapelon, Francoise | Bueno-de-Mesquita, H.Bas | Trichopoulos, Dimitrios | Khaw, Kay-Tee | Johansson, Mikael | Weiderpass, Elisabete | Tjønneland, Anne | Riboli, Elio | Lathrop, Mark | Scelo, Ghislaine | Albanes, Demetrius | Caporaso, Neil E. | Ye, Yuanqing | Gu, Jian | Wu, Xifeng | Spitz, Margaret R. | Dienemann, Hendrik | Rosenberger, Albert | Su, Li | Matakidou, Athena | Eisen, Timothy | Stefansson, Kari | Risch, Angela | Chanock, Stephen J. | Christiani, David C. | Hung, Rayjean J. | Brennan, Paul | Landi, Maria Teresa | Houlston, Richard S. | Amos, Christopher I.
Nature genetics  2014;46(7):736-741.
We conducted imputation to the 1000 Genomes Project of four genome-wide association studies of lung cancer in populations of European ancestry (11,348 cases and 15,861 controls) and genotyped an additional 10,246 cases and 38,295 controls for follow-up. We identified large-effect genome-wide associations for squamous lung cancer with the rare variants of BRCA2-K3326X (rs11571833; odds ratio [OR]=2.47, P=4.74×10−20) and of CHEK2-I157T (rs17879961; OR=0.38 P=1.27×10−13). We also showed an association between common variation at 3q28 (TP63; rs13314271; OR=1.13, P=7.22×10−10) and lung adenocarcinoma previously only reported in Asians. These findings provide further evidence for inherited genetic susceptibility to lung cancer and its biological basis. Additionally, our analysis demonstrates that imputation can identify rare disease-causing variants having substantive effects on cancer risk from pre-existing GWAS data.
doi:10.1038/ng.3002
PMCID: PMC4074058  PMID: 24880342
4.  Short telomere lengths in peripheral blood leukocytes are associated with an increased risk of oral premalignant lesion and oral squamous cell carcinoma 
Cancer  2013;119(24):10.1002/cncr.28367.
Background
Oral premalignant lesions (OPLs) are precursors of oral squamous cell carcinoma (OSCC). Short telomeres in peripheral blood leukocytes are associated with increased risks of several cancers. However, whether short leukocyte telomere length (LTL) predisposes to OPL and OSCC is unclear.
Methods
LTLs were measured in PBLs of 266 patients with OPL (N=174) or OSCC (N=92) at diagnosis and 394 age- and gender-matched control subjects. The association between LTL and OPL or OSCC risk, as well as the interaction of telomere length, cigarette smoking and alcohol drinking on OPL or OSCC risk were analyzed.
Results
The age-adjusted relative LTL was the shortest in OSCC (1.64±0.29), intermediate in OPL (1.75±0.43), and longest in controls (1.82±0.36) (P for trend < 0.001). When dichotomized at the median value in controls, adjusting for age, gender, smoking and alcohol drinking status, the odds ratio (OR) for OPL and OSCC risks associated with short LTL was 2.03 (95% CI = 1.29–3.21) and 3.47 (95% CI = 1.84–6.53), respectively, with significant dose-response effects for both associations. Among 174 OPL patients, 23 progressed to OSCC and the mean LTL was shorter than in progressors than non-progressors (1.66±0.35 vs. 1.77±0.44), although the difference did not reach statistical significance (P=0.258) likely due to the small number of progressors. Interaction analysis shows that short LTL, smoking, and alcohol drinking are independent risk factors for OPL and OSCC.
Conclusion
Short LTL is associated with increased risks of developing OPL and OSCC and likely predisposes to the malignant progression of OPL patients.
doi:10.1002/cncr.28367
PMCID: PMC3855186  PMID: 24105340
Telomere length; peripheral blood leukocyte; oral premalignant lesion; oral squamous cell carcinoma; smoking; alcohol drinking
5.  Genome-wide methylation analysis shows similar patterns in Barrett’s esophagus and esophageal adenocarcinoma 
Carcinogenesis  2013;34(12):2750-2756.
Barrett’s esophagus (BE) is a precursor of esophageal adenocarcinoma (EAC). To identify novel tumor suppressors involved in esophageal carcinogenesis and potential biomarkers for the malignant progression of BE, we performed a genome-wide methylation profiling of BE and EAC tissues. Using Illumina’s Infinium HumanMethylation27 BeadChip microarray, we examined the methylation status of 27 578 CpG sites in 94 normal esophageal (NE), 77 BE and 117 EAC tissue samples. The overall methylation of CpG sites within the CpG islands was higher, but outside of the CpG islands was lower in BE and EAC tissues than in NE tissues. Hierarchical clustering analysis showed an excellent separation of NE tissues from BE and EAC tissues; however, the clustering of BE and EAC tissues was less clear, suggesting that methylation occurs early during the progression of EAC. We confirmed many previously reported hypermethylated genes and identified a large number of novel hypermethylated genes in BE and EAC tissues, particularly genes encoding ADAM (A Disintegrin And Metalloproteinase) peptidase proteins, cadherins and protocadherins, and potassium voltage-gated channels. Pathway analysis showed that a number of channel and transporter activities were enriched for hypermethylated genes. We used pyrosequencing to validate selected candidate genes and found high correlations between the array and pyrosequencing data (rho > 0.8 for each validated gene). The differentially methylated genes and pathways may provide biological insights into the development and progression of BE and become potential biomarkers for the prediction and early detection of EAC.
doi:10.1093/carcin/bgt286
PMCID: PMC3845893  PMID: 23996928
6.  Cyclin D1 and Cancer Development in Laryngeal Premalignancy Patients 
In a previous trial, we found that combined 13-cis retinoic acid (13-cRA), interferon-α and α-tocopherol more effectively reversed advanced premalignant lesions of the larynx than of the oral cavity and that cyclin D1 (CD1)G/A870 single nucleotide polymorphism correlated with cancer risk. We conducted the present trial primarily to confirm the clinical activity of the combination in advanced laryngeal premalignancy and to confirm and extend our findings on CD1, both genotype and protein expression, in association with cancer risk in this setting. Twenty-seven moderate-to-severe laryngeal dysplasia patients underwent induction with combined 13-cRA daily, α-interferon twice weekly, and α-tocopherol daily for one year; 14 non-progressing patients then were randomized to maintenance fenretinide or placebo for two years. During induction, 2 patients had pathological complete responses, 6 had partial responses (30% overall response rate), and 5 developed laryngeal cancer. There were no significant differences between maintenance fenretinide and placebo in response or cancer rates. Ten patients developed cancer overall. Twenty-four patients were evaluated for the CD1 G/A870 genotype, and 23 for pre- and post-treatment CD1 protein expression. Consistent with our earlier report, shorter cancer-free survival was associated with the CD1 AA/AG genotype (p = 0.05). Extending our earlier work, high CD1 expression was associated with worse cancer-free survival overall (p= 0.04) and within each CD1 genotype group. These findings support CD1 genotype and protein expression as important risk markers for laryngeal cancer and suggest future trials targeting upstream regulators of CD1 transcription.
doi:10.1158/1940-6207.CAPR-08-0111
PMCID: PMC4243520  PMID: 19139013
Premalignant lesions; larynx; biochemoprevention; cyclin D1 genotype; cyclin D1 protein expression
7.  Association of mitochondrial DNA copy number in peripheral blood leukocytes with risk of esophageal adenocarcinoma 
Carcinogenesis  2013;34(11):2521-2524.
Alterations of mitochondrial DNA (mtDNA) have been associated with the risk of a number of human cancers; however, the relationship between mtDNA copy number in peripheral blood leukocytes and the risk of esophageal adenocarcinoma (EAC) has not been reported. In this study, we determined relative mtDNA copy number in peripheral blood leukocytes of 218 EAC cases and 218 frequency-matched controls. We calculated odds ratios and 95% confidence intervals using unconditional logistic regression, adjusting for age, sex and smoking status. MtDNA copy number was significantly lower in cases than in controls (mean ± SD, 1.16 ± 0.30 versus 1.27 ± 0.43, P = 0.002). Dichotomized at the median value of mtDNA copy number in the controls, low mtDNA copy number was significantly associated with an increased risk of EAC (odds ratio: 1.55, 95% confidence interval: 1.05–2.29). A significant dose–response relationship was observed between mtDNA copy number and risk of EAC in quartile analysis. Our results suggest that low mtDNA copy number in peripheral blood leukocytes is associated with increased susceptibility to EAC.
doi:10.1093/carcin/bgt230
PMCID: PMC3810839  PMID: 23803692
8.  γ-H2AX level in peripheral blood lymphocytes as a risk predictor for bladder cancer 
Carcinogenesis  2013;34(11):2543-2547.
Identification of susceptibility to double-strand breaks (DSBs) may provide valuable information about individual bladder cancer (BC) risk. The formation of γ-H2AX foci is a highly sensitive marker for DNA DSBs induction. We assessed whether levels of γ-H2AX in peripheral blood lymphocytes (PBL) obtained after stimulation by ionizing radiation (IR) are able to predict BC risk. Patients were enrolled from an ongoing BC case–control study. Baseline- and IR-induced H2AX phosphorylation was assessed in PBL from 174 newly diagnosed and untreated BC patients and from 174 matched control subjects by a novel, image-based, high-throughput phenotypic assay. The ratio of γ-H2AX level of IR-treated cells to that of non-treated cells (baseline) was used as the parameter to assess the sensitivity to the mutagen. The mean γ-H2AX ratios were significantly higher for cases than for controls (1.43±0.14 versus 1.35±0.12; P = 8.45×10−8). This trend was irrespective of age, sex and smoking status. The risk estimates of BC for induced DSBs by tertile distributions in controls showed also a significant trend for increased risk at the highest tertile for the whole cohort (odds ratio = 5.16; 95% confidence interval = 2.69, 9.89; P = 7.78 × 10− 7) as well as for each category. Our findings suggest that a higher susceptibility to induction of DSBs as measured by the γ-H2AX assay is significantly associated with an increased risk for BC. This might help to identify individuals at high risk for this cancer, adding new perspectives to established epidemiological and genetic risk factors. Further research of the role of γ-H2AX in biological processes of BC is warranted.
doi:10.1093/carcin/bgt270
PMCID: PMC3810842  PMID: 23946494
9.  Symptom Clusters of Pain, Depressed Mood, and Fatigue in Lung Cancer: Assessing the Role of Cytokine Genes 
PURPOSE
Symptom clusters, the multiple, co-occurring symptoms experienced by cancer patients, are debilitating and affects quality of life. We assessed if a panel of immune-response genes may underlie the co-occurrence of severe pain, depressed mood and fatigue and help identify patients with severe versus non-severe symptom clusters.
METHODS
Symptoms were assessed at presentation, prior to cancer treatment in 599 newly diagnosed lung cancer patients. We applied cluster analyses to determine the patients with severe versus non-severe symptom clusters of pain, depressed mood, and fatigue.
RESULTS
Two homogenous clusters were identified. One hundred sixteen patients (19%) comprised the severe symptom cluster, reporting high intensity of pain, depressed mood and fatigue and 183 (30%) patients reported low intensity of these symptoms. Using Bayesian model averaging methodology, we found that of the 55 SNPs assessed, an additive effect of mutant alleles in ENOS (-1474 T/A) (Posterior Probability of Inclusion (PPI) = 0.78, OR = 0.54, 95% CI = (0.31, 0.93); IL1B T-31C (PPI = 0.72, OR = 0.55, 95% CI = (0.31, 0.97)); TNFR2 Met196Arg (PPI = 0.70; OR=1.85;95%CI=(1.03,3.36)); PTGS2 exon 10+837T>C (PPI = 0.69, OR = 0.54, 95%CI = (0.28, 0.99)); and IL10RB Lys47Glu (PPI = 0.68; OR=1.74; 95%CI=(1.04,2.92)) were predictive for symptom clusters.
CONCLUSIONS
Genetic polymorphisms may facilitate identification of high risk patients and development of individualized symptom therapies.
doi:10.1007/s00520-013-1885-5
PMCID: PMC3923575  PMID: 23852407
pain; depression; fatigue; cytokines; symptoms; genes; epidemiology; lung cancer; SNPs
10.  Risk assessment of esophageal adenocarcinoma using γ-H2AX assay 
Background
Mutagen-induced DNA damage as measured in peripheral blood lymphocytes (PBLs) has been associated with increased risks of cancers. The formation of γ-H2AX is an early cellular response to DNA double-strand breaks (DSBs). We hypothesize that higher level of radiation-induced γ-H2AX in PBLs may be associated with an increased risk of esophageal adenocarcinoma (EAC).
Methods
Laser scanning cytometer–based immunocytochemical method was used to measure baseline and irradiation-induced γ-H2AX levels in PBLs from 211 EAC patients and 211 healthy controls. The ratio of induced γ-H2AX level to baseline level was used to evaluate individual susceptibility to DSBs. Relative risks for EAC associated with γ-H2AX were assessed by multivariable logistic regression analysis.
Results
Radiation-induced γ-H2AX level and the γ-H2AX ratio were significantly higher in cases than in controls. Dichotomized at the median in controls, a significantly increased risk for EAC was observed in association with high γ-H2AX ratio (odds ratio=2.94, 95% confidence interval=1.83–4.72). Quartile analyses showed significant dose-response associations between higher γ-H2AX ratio and increased risk of EAC (P for trend, 1.64E-06). In addition, joint effect between γ-H2AX ratio and smoking was observed: smokers who had high γ-H2AX ratio exhibited the highest risk of EAC (OR =5.53, 95% CI: 2.71–11.25) compared to never-smokers with low γ-H2AX ratio.
Conclusion
Radiation-induced DNA damage assessed by γ-H2AX ratio is associated with an increased risk of EAC.
Impact
γ-H2AX assay is a new and robust method to measure DSB damage in PBLs, which can be used to assess mutagen sensitivity and EAC risk.
doi:10.1158/1055-9965.EPI-13-0485
PMCID: PMC3824382  PMID: 23904462
Double strand break; γ-H2AX; mutagen sensitivity assay; esophageal cancer risk
11.  Genetic polymorphisms in microRNA-related genes as predictors of clinical outcomes in colorectal adenocarcinoma patients 
Purpose
To evaluate the effects of single-nucleotide polymorphisms (SNPs) in microRNA-related genes on clinical outcomes in colorectal cancer (CRC) patients receiving first-line fluoropyrimidine-based chemotherapy.
Experimental Design
Forty-one SNPs in 26 microRNA-related genes were genotyped in 1,097 CRC patients recruited at the University of Texas MD Anderson Cancer Center. Patients were enrolled between 1990 and 2008 and last follow-up was in 2010. The associations between genotypes and recurrence-free survival (RFS), progression-free survival (PFS), and overall survival (OS) stratified by clinical stage were analyzed in 741 newly diagnosed patients (diagnosed within 1 year) and replicated the findings in additional 356 patients.
Results
In patients with stage III disease, mir608:rs4919510 was associated with increased risk for both recurrence (HR=2.72; 95%CI, 1.38 to 5.33) and death (HR=3.53; 95%CI, 1.42 to 8.73). The associations were confirmed in the replication set and the combined HR for training and replication sets was 1.94 (95% CI, 1.31 to 2.86) for recurrence and 2.35 (95%CI, 1.40 to 3.93) for death, respectively. The mir219-1:rs213210 showed consistent association with death in the training set (HR=3.86; 95%CI, 1.33 to11.22), the replication set (HR = 3.33; 95% CI, 1.39 to 7.98) and combined dataset (HR = 3.53; 95% CI, 1.80 to 6.95). In combined analysis of these two SNPs, patients carrying the variant genotypes at both sites exhibited a 5.6 fold increased risk of death.
Conclusion
Genetic polymorphisms in the microRNA pathway may predict prognosis in stage III CRC patients treated with fluoropyrimidine-based chemotherapy.
doi:10.1158/1078-0432.CCR-11-2951
PMCID: PMC4141857  PMID: 22661538
colorectal cancer; polymorphism; microRNA; chemotherapy; recurrence; survival
12.  Genetic Variations in Interleukin-8 and Interleukin-10 Are Associated With Pain, Depressed Mood, and Fatigue in Lung Cancer Patients 
Context
A report by the National Cancer Institute identified that an important gap in symptom research is the investigation of multiple symptoms of cancer that might identify common biological mechanisms among cancer-related symptoms.
Objectives
We applied novel statistical methods to assess whether variants of 37 inflammation genes may serve as biologic markers of risk for severe pain, depressed mood, and fatigue in non-Hispanic white patients with non-small cell lung cancer.
Methods
Pain, fatigue, and depressed mood were assessed prior to cancer treatment. We used a generalized, multivariate, classification tree approach to explore the influence of single nucleotide polymorphisms in the inflammation genes in pain, depressed mood, and fatigue in lung cancer patients.
Results
Among patients with advanced-stage disease, IL-8-T251A was the most relevant genetic factor for pain (odds ratio [OR]=2.18, 95% confidence interval [CI]=1.34,3.55; P=0.001), depressed mood (OR=0.37, 95% CI=0.14,1.0), and fatigue (OR=2.07, 95% CI=1.16,3.70). Among those with early-stage NSCLC, variants in the IL-10 receptor were relevant for fatigue among women. Specifically, women with genotype Lys_Glu or Glu_Glu in the IL-10 gene had a 0.49 times lower risk of severe fatigue compared with those with genotype Lys_Lys (OR=0.49, 95% CI=0.25, 0.92; P=0.027). Among men with early-stage lung cancer, a marginal significance was observed for IL-1A C-889T, C/T or T/T genotype: these men had a lower risk of severe fatigue compared with those with genotype C/C (OR=0.38, 95% CI=0.13, 1.06).
Conclusion
The interaction of multiple inflammation genes, along with non-genetic factors, underlies the occurrence of symptoms. IL-8 and IL-10 may serve as potential targets for treating multiple symptoms of cancer.
doi:10.1016/j.jpainsymman.2012.07.019
PMCID: PMC3578112  PMID: 23149083
Pain; depression; fatigue; cytokines; symptoms; genes
13.  Pathway-based serum microRNA profiling and survival in patients with advanced-stage non-small cell lung cancer 
Cancer research  2013;73(15):4801-4809.
This study was designed to identify TGF-β signaling pathway-related serum microRNAs (miRNAs) as predictors of survival in advanced non-small cell lung cancer (NSCLC). Serum samples from 391 patients with advanced NSCLC were collected prior to treatment. Global miRNA microarray expression profiling based on sera from four patients with good survival (>24 months) and four patients with poor survival (<6 months) was used to identify 140 highly expressed serum miRNAs, among which 35 miRNAs had binding sites within the 3’-untranslated regions of a panel of 11 genes in the TGF-β signaling pathway and were assayed by quantitative RT-PCR for their associations with survival in a training (n=192) and testing set (n=191). Out of the 35 miRNAs, survival analysis using Cox regression model identified 17 miRNAs significantly associated with 2-year patient survival. MiR-16 exhibited the most statistically significant association: high expression of miR-16 was associated with a significantly better survival (adjusted hazard ratio = 0.4, 95% confidence interval: 0.3–0.5). A combined 17-miRNA risk score was created that was able to identify patients at the highest risk of death. Those with a high risk score had a 2.5-fold increased risk of death compared to those with a low risk score (95% CI=1.8–3.4, P=1.1×10−7). This increase in risk of death was corresponding to an 7.8 month decrease in median survival time (P=9.5×10−14). Our results suggest that serum miRNAs could serve as predictors of survival for advanced NSCLC.
doi:10.1158/0008-5472.CAN-12-3273
PMCID: PMC3760306  PMID: 23774211
serum miRNA; TGF-β; survival; NSCLC
14.  Testicular germ cell tumor susceptibility associated with the UCK2 locus on chromosome 1q23 
Human Molecular Genetics  2013;22(13):2748-2753.
Genome-wide association studies (GWASs) have identified multiple common genetic variants associated with an increased risk of testicular germ cell tumors (TGCTs). A previous GWAS reported a possible TGCT susceptibility locus on chromosome 1q23 in the UCK2 gene, but failed to reach genome-wide significance following replication. We interrogated this region by conducting a meta-analysis of two independent GWASs including a total of 940 TGCT cases and 1559 controls for 122 single-nucleotide polymorphisms (SNPs) on chromosome 1q23 and followed up the most significant SNPs in an additional 2202 TGCT cases and 2386 controls from four case–control studies. We observed genome-wide significant associations for several UCK2 markers, the most significant of which was for rs3790665 (PCombined = 6.0 × 10−9). Additional support is provided from an independent familial study of TGCT where a significant over-transmission for rs3790665 with TGCT risk was observed (PFBAT = 2.3 × 10−3). Here, we provide substantial evidence for the association between UCK2 genetic variation and TGCT risk.
doi:10.1093/hmg/ddt109
PMCID: PMC3674801  PMID: 23462292
15.  Genome-wide association study of genetic predictors of overall survival for non-small cell lung cancer in never smokers 
Cancer research  2013;73(13):4028-4038.
To identify the genetic factors that influence overall survival in never smokers who have non-small cell lung cancer (NSCLC), we performed a consistency meta-analysis study utilizing genome-wide association approaches for overall survival in 327 never smoker NSCLC patients from the MD Anderson Cancer Center and 293 cases from the Mayo Clinic. We then performed a two-pronged validation of the top 25 variants that included additional validation in 1,256 NSCLC patients from Taiwan and assessment of expression quantitative trait loci (eQTL) and differential expression of genes surrounding the top loci in 70 tumors and matched normal tissues. A total of 94 loci were significant for overall survival in both MD Anderson and Mayo studies in the consistency meta-analysis phase, with the top 25 variants reaching a p-value of 10−6. Two variants of these 25 were also significant in the Taiwanese population: rs6901416 (HR:1.44, 95%CI:1.01-2.06) and rs10766739 (HR:1.23, 95%CI:1.00-1.51). These loci resulted in a reduction in median survival time of at least 8 and 5 months in three populations, respectively. An additional six variants (rs4237904, rs7976914, rs4970833, rs954785, rs485411, and rs10906104) were validated through eQTL analysis that identified significant correlations with expression levels of six genes (LEMD3, TMBIM, ATXN7L2, SHE, ITIH2, and NUDT5, respectively) in normal lung tissue. These genes were also significantly differentially expressed between the tumor and normal lung. These findings identify several novel, candidate prognostic markers for NSCLC in never smokers, with eQTL analysis suggesting a potential biological mechanism for a subset of these observed associations.
doi:10.1158/0008-5472.CAN-12-4033
PMCID: PMC3719971  PMID: 23704207
16.  Integrative genomic characterization of oral squamous cell carcinomaidentifies frequent somatic drivers 
Cancer discovery  2013;3(7):10.1158/2159-8290.CD-12-0537.
The survival of patients with oral squamous cell carcinoma (OSCC) has not changed significantly in several decades, leading clinicians and investigators to search for promising molecular targets. To this end, we performed comprehensive genomic analysis of gene expression, copy number, methylation and point mutations in OSCC. Integrated analysis revealed more somatic events than previously reported, identifying four major driver pathways (mitogenic signaling, Notch, cell cycle, TP53) and two additional key genes (FAT1, CASP8). The Notch pathway was defective in 66% of patients, and in follow-up studies of mechanism, functional NOTCH1 signaling inhibited proliferation of OSCC cell lines. Frequent mutation of CASP8 defines a new molecular subtype of OSCC with few copy number changes. Although genomic alterations are dominated by loss of tumor suppressor genes, 80% of patients harbored at least one genomic alteration in a targetable gene, suggesting that novel approaches to treatment may be possible for this debilitating disease.
doi:10.1158/2159-8290.CD-12-0537
PMCID: PMC3858325  PMID: 23619168
Integrated genomics; head and neck/oral cancers; NOTCH1; CASP8
17.  Long telomeres in peripheral blood leukocytes are associated with an increased risk of soft tissue sarcoma 
Cancer  2013;119(10):10.1002/cncr.27984.
Background
Human telomeres consisting of long, tandem repeats of the nucleotide sequence TTAGGG at the chromosome ends are essential for maintaining chromosomal stability. Previous epidemiologic studies have indicated that shorter telomere length in peripheral blood leukocytes (PBLs) is associated with the development of many cancers. However, the relationship between PBL telomere length and the risk of soft tissue sarcoma (STS) has not been investigated.
Methods
We determined the relative telomere length (RTL) in PBLs using real-time polymerase chain reaction (PCR) in this case-control study. The study participants included 137 patients with histologically confirmed STS (cases) with no prior chemotherapy or radiotherapy and 137 healthy controls frequency-matched to cases on age, gender, and ethnicity.
Results
The cases had significantly longer RTL than controls did (1.46 ± 0.42 for cases vs.1.15 ± 0.39 for controls, P < 0.001). Using median RTL in the controls as a cutoff, individuals with long telomere length were associated with a significantly increased risk of STS compared with those with short telomere length (adjusted odds ratio =4.71; 95% confidence interval, 2.63–8.44). When participants were categorized further into three or four groups according to the tertile or quartile RTL values of healthy controls, we observed a significant dose-response relationship between longer RTL and increased risks of STS.
Conclusions
The present study provides the first epidemiologic evidence that longer telomere length in PBLs is significantly associated with an increased risk of STS, potentially suggesting an important role for telomere maintenance in STS development.
doi:10.1002/cncr.27984
PMCID: PMC3807211  PMID: 23408253
telomere length; peripheral blood leukocyte (PBL); soft tissue sarcoma (STS); cancer risk
18.  Genetic Variations in Regulator of G-Protein Signaling (RGS) Confer Risk of Bladder Cancer 
Cancer  2013;119(9):1643-1651.
Background
Alterations in the RGS pathway have been implicated in several cancers; therefore, we determined their role in overall bladder cancer risk, recurrence, progression and survival.
Methods
This is a case-control series of 803 bladder cancer patients with a frequency-matched cohort of 803 healthy individuals. We evaluated 95 SNPs in 17 RGS genes for association with overall bladder cancer risk, recurrence and progression in patients with non-muscle invasive bladder cancer (NMIBC), and death in patients with muscle invasive bladder cancer (MIBC). Cumulative effects and Classification and Regression Tree analyses were performed for SNPs associated with overall bladder cancer risk. Kaplan-Meier graphs were created to evaluate survival differences in patients with MIBC.
Results
Rs10759 on the RGS4 gene demonstrated the highest association with overall bladder cancer risk conferring a 0.77 fold reduced risk with the increasing number of variant alleles (P<0.001). Cumulative effects analysis, including all five significant SNPs, demonstrated increasing risk with the number of unfavorable genotypes (OR 4.13, 95% CI 2.14–7.98). Eleven and thirteen SNPs were identified to be associated with recurrence and progression in NMIBC, respectively. Of the 10 SNPs associated with death in MIBC, rs2344673 in an additive model was the most significant and associated with a decreased median survival of 13.3 months compared to 81.9 months in individuals without a variant allele.
Conclusion
Genetic variations in the RGS pathway are associated with overall risk of bladder cancer, recurrence and progression in patients with NMIBC, and risk of death in patients with MIBC.
doi:10.1002/cncr.27871
PMCID: PMC4004376  PMID: 23529717
Bladder Cancer; Regulator of G-protein signaling; single nucleotide polymorphism
19.  Genetic variations in micro-RNA biogenesis genes and clinical outcomes in non-muscle-invasive bladder cancer 
Carcinogenesis  2013;34(5):1006-1011.
Micro-RNAs (miRNAs) are small non-coding RNA molecules, which can act as either oncogenes or tumor suppressors. Dysregulated expression of miRNA genes have been implicated in the development of many different cancers. We hypothesize that genetic variations in miRNA biogenesis genes may be associated with the prognosis of bladder cancer. We genotyped 76 single nucleotide polymorphisms (SNPs) in eight miRNA biogenesis genes in 421 patients with non-muscle-invasive bladder cancer (NMIBC). We analyzed the associations of SNPs with recurrence and progression in all patients as well as stratified by treatment: transurethral resection (TUR) alone or TUR plus intravesical bacillus Calmette–Guérin (BCG) instillation. Two SNPs were significantly associated with tumor recurrence in TUR only subgroup after adjustment for multiple comparisons (Q < 0.1). The most significant SNP was rs197412 in DDX20: the variant allele conferred a decreased risk of recurrence [hazard ratio (HR) = 0.58, 95% confidence interval (95% CI) = 0.40–0.82]. This SNP was validated in a separate group of 586 NMIBC patients and the pooled HR was 0.62 (95% CI = 0.48–0.81, P < 0.001). Two linked SNPs (rs2073778 and rs720012) in DGCR8 showed significant association with tumor progression (HR = 4.00, 95% CI = 1.53–10.46, P = 0.005). A strong gene-dosage effect was observed with higher risk for tumor recurrence and progression with increasing number of unfavorable genotypes. Haplotype and survival tree analyses further characterized the association of miRNA-related SNPs with tumor recurrence and progression. Taken together, our results indicate that genetic variants in miRNA biogenesis pathway may influence bladder cancer clinical outcome in NMIBC patients.
doi:10.1093/carcin/bgt006
PMCID: PMC3643413  PMID: 23322153
20.  Polymorphisms in the XRCC1 gene modify survival of bladder cancer patients treated with chemotherapy 
Survival of bladder cancer patients depends on several factors including disease stage and grade at diagnosis, age, health status of the patient and the applied treatment. Several studies investigated the role of DNA repair genetic variants in cancer susceptibility, but only few studies investigated their role in survival and response to chemotherapy for bladder cancer. We genotyped 28 single nucleotide polymorphisms (SNP) in DNA repair genes in 456 bladder cancer patients, reconstructed haplotypes and calculated a score for combinations of the SNPs. We estimated Hazard Ratios (adjHR) for time to death. Among patients treated with chemotherapy, variant alleles of five SNPs in the XRCC1 gene conferred better survival (rs915927 adjHR 0.55 (95%CI 0.32–0.94); rs76507 adjHR 0.48 (95%CI 0.27–0.84); rs2854501 adjHR 0.25 (95%CI 0.12–0.52); rs2854509 adjHR 0.21 (95%CI 0.09–0.46); rs3213255 adjHR 0.46 (95%CI 0.26–0.80). In this group of patients, an increasing number of variant alleles in a XRCC1 gene score were associated with a better survival (26% decrease of risk of death for each additional variant allele in XRCC1). By functional analyses we demonstrated that the previous XRCC1 SNPs confer lower DNA repair capacity. This may support the hypothesis that survival in these patients may be modulated by the different DNA repair capacity determined by genetic variants. Chemotherapy treated cancer patients bearing an increasing number of “risky” alleles in XRCC1 gene had a better survival, suggesting that a proficient DNA repair may result in resistance to therapy and shorter survival. This finding may have clinical implications for the choice of therapy.
doi:10.1002/ijc.28186
PMCID: PMC3804126  PMID: 23553206
bladder cancer; chemotherapy; DNA repair genes; survival; XRCC1
21.  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
22.  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
23.  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
24.  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
25.  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

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