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1.  Frequent mutation of the PI3K pathway in head and neck cancer defines predictive biomarkers 
Cancer discovery  2013;3(7):761-769.
Genomic findings underscore the heterogeneity of head and neck squamous cell carcinoma (HNSCC)(1, 2). Identification of mutations that predict therapeutic response would be a major advance. We determined the mutationally altered, targetable mitogenic pathways in a large HNSCC cohort. Analysis of whole-exome sequencing data from 151 tumors revealed the PI3K pathway to be the most frequently mutated oncogenic pathway (30.5%). PI3K pathway-mutated HNSCC tumors harbored a significantly higher rate of mutations in known cancer genes. In a subset of HPV-positive tumors, PIK3CA or PIK3R1 was the only mutated cancer gene. Strikingly, all tumors with concurrent mutation of multiple PI3K pathway genes were advanced (stage IV), implicating concerted PI3K pathway aberrations in HNSCC progression. Patient-derived tumorgrafts with canonical and non-canonical PIK3CA mutations were sensitive to an m-TOR/PI3K inhibitor (BEZ-235) in contrast to PIK3CA wildtype tumorgrafts. These results suggest that PI3K pathway mutations may serve as predictive biomarkers for treatment selection.
doi:10.1158/2159-8290.CD-13-0103
PMCID: PMC3710532  PMID: 23619167
PI3K; mutation; BEZ-235; head and neck cancer
2.  CYP2A6 Genotype and Smoking Behavior in Current Smokers Screened for Lung Cancer 
Substance use & misuse  2013;48(7):490-494.
Functional CYP2A6 genetic variation partially determines nicotine metabolism. In 2005, we examined functional CYP2A6 variants associated with reduced metabolism (CYP2A6*2, CYP2A6*9, CYP2A6*4), smoking history, and change in smoking in 878 adult smokers undergoing lung cancer screening in an urban setting. At one year, 216 quit smoking for more than 30 days while 662 continued smoking. Compared to subjects who smoked 30 cigarettes per day at baseline, the odds of a reduced metabolism genotype was 52% higher in subjects smoking 20–29 cigarettes per day and 86% higher in subjects smoking less than 20 cigarettes per day (p-trend = 0.016). Reduced metabolism genotypes appeared unrelated to quitting. Though related to smoking dose, CYP2A6 may not influence cessation.
doi:10.3109/10826084.2013.778280
PMCID: PMC3788637  PMID: 23528144
smoking cessation; smoking initiation; cigarette smoking; genetics; cytochrome P450; nicotine metabolism
3.  Genetic variability in DNA repair and cell cycle control pathway genes and risk of smoking-related lung cancer 
Molecular carcinogenesis  2011;51(Suppl 1):E11-E20.
DNA repair and cell cycle control play an important role in the repair of DNA damage caused by cigarette smoking. Given this role, functionally relevant single nucleotide polymorphisms (SNPs) in genes in these pathways may well affect the risk of smoking-related lung cancer. We examined the relationship between 240 SNPs in DNA repair and cell cycle control pathway genes and lung cancer risk in a case-control study of white current and ex-cigarette smokers (722 cases and 929 controls). Additive, dominant and recessive genetic models were evaluated for each SNP. A genetic risk summary score was also constructed. Odds ratios (OR) for lung cancer risk and 95% confidence intervals (95% CI) were estimated using logistic regression models. Thirty-eight SNPs were associated with lung cancer risk in our study population at P<0.05. The strongest associations were observed for rs2074508 in GTF2H4 (Padditive=0.003), rs10500298 in LIG1 (Precessive=2.7×10−4), rs747658 and rs3219073 in PARP1 (rs747658: Padditive=5.8×10−5; rs3219073: Padditive=4.6×10−5), and rs1799782 and rs3213255 in XRCC1 (rs1799782: Pdominant=0.006; rs3213255: Precessive=0.004). Compared to individuals with first quartile (lowest) risk summary scores, individuals with third and fourth quartile summary score results were at increased risk for lung cancer (OR: 2.21, 95% CI: 1.66–2.95 and OR: 3.44, 95% CI: 2.58–4.59, respectively; Ptrend<0.0001). Our data suggests that variation in DNA repair and cell cycle control pathway genes is associated with smoking-related lung cancer risk. Additionally, combining genotype information for SNPs in these pathways may assist in classifying current and ex-cigarette smokers according to lung cancer risk.
doi:10.1002/mc.20858
PMCID: PMC3289753  PMID: 21976407
SNP; case-control; lung cancer
4.  Team Building: Electronic Management-Clinical Translational Research (eM-CTR) Systems 
Classical drug exposure: response studies in clinical pharmacology represent the quintessential prototype for Bench to Bedside-Clinical Translational Research. A fundamental premise of this approach is for a multidisciplinary team of researchers to design and execute complex, in-depth mechanistic studies conducted in relatively small groups of subjects. The infrastructure support for this genre of clinical research is not well-handled by scaling down of infrastructure used for large Phase III clinical trials. We describe a novel, integrated strategy, whose focus is to support and manage a study using an Information Hub, Communication Hub, and Data Hub design. This design is illustrated by an application to a series of varied projects sponsored by Special Clinical Centers of Research in chronic obstructive pulmonary disease at the University of Pittsburgh. In contrast to classical informatics support, it is readily scalable to large studies. Our experience suggests the culture consequences of research group self-empowerment is not only economically efficient but transformative to the research process.
doi:10.1111/j.1752-8062.2009.00157.x
PMCID: PMC3687802  PMID: 20443940
institutional management teams; organization and administration; information services; information storage and retrieval
5.  CASE–CONTROL STUDY OF ORAL AND OROPHARYNGEAL CANCER IN WHITES AND GENETIC VARIATION IN EIGHT METABOLIC ENZYMES 
Head & neck  2008;30(9):1139-1147.
Background
Genetic variation in xenobiotic metabolizing enzymes may explain differing susceptibilities to the cancer causing effects of tobacco and alcohol.
Methods
We compared 203 oral squamous cell carcinoma cases and 416 controls for single nucleotide polymorphisms (SNPs) in 8 genes (CYP1A1, CYP2E1, MPO, mEH, GSTM1, GSTT1, GSTP1, and NAT2). Except for NAT2, genotype frequencies were similar in the 2 groups. We classified subjects as fast or slow NAT2 acetylators genotyping 13 NAT2 SNPs.
Results
Fast acetylators were overrepresented in cases (53.7%) compared with controls (43.9%; odds ratio (OR) 1.55, 95% confidence interval (CI) 1.08–2.20; p value = .03). Gene–gene interaction testing suggested several cancer-NAT2 associations, with association strongest among persons without a CYP1A1 variant (*2C or *4) allele (OR 1.77, 95% CI 1.20–2.60, p value = .03) or with a variant MPO (463A) allele (OR 2.38, 95% CI 1.34–4.21, p value = .05).
Conclusion
These results implicate fast NAT2 acetylation as a risk factor for oral cancer.
doi:10.1002/hed.20867
PMCID: PMC3627181  PMID: 18642288
tobacco; oral cancer; polymorphism; metabolizing enzymes; susceptibility
6.  An empirical workflow for genome-wide single nucleotide polymorphism-based predictive modeling 
Technology is constantly evolving, necessitating the development of workflows for efficient use of high-dimensional data. We develop and test an empirical workflow for predictive modeling based on single nucleotide polymorphisms (SNP) from genome-wide association study (GWAS) datasets. To this aim, we use as a case study SNP-based prediction of survival for non-small cell lung cancer (NSCLC) with a Bayesian rule learner system (BRL+). Lung cancer is a leading cause of mortality. Standard treatment for early stages of NSCLC is surgery. Adjuvant chemotherapy would be beneficial for patients with early recurrence; consequently, we need models capable of such prediction. This workflow outlines the challenges involved in processing GWAS datasets from one popular platform (Affymetrix®), from the results files of the hybridization experiment to the model construction. Our results show that our workflow is feasible and efficient for processing such data while also yielding SNP based models with high predictive accuracy over cross validation.
PMCID: PMC3814469  PMID: 24303297
7.  Effects of ERCC2 Lys751Gln (A35931C) and CCND1 (G870A) polymorphism on outcome of advanced-stage squamous cell carcinoma of the head and neck are treatment dependent 
Background
Germline variation in DNA damage response may explain variable treatment outcomes from squamous cell carcinoma of the head and neck (SCCHN). Grouping patients according to stage and radiation treatment, we compared SCCHN survival according to ERCC2 A35931C (Lys751Gln, rs13181) and CCND1 G870A (Pro241Pro, rs9344) genotypes.
Methods
Recruiting a hospital-based SCCHN case series (all white, 24.7% female, mean age 58.4 years), this treatment outcome cohort study genotyped n=275 stage III-IV cases initially treated with radiation (with or without chemotherapy) and n=80 stage III-IV and n=130 stage I-II cases initially treated without radiation or chemotherapy and used Kaplan-Meier and Cox regression analysis to compare genotype groups according to overall, disease-specific, progression-free, and recurrence-free survival.
Results
ERCC2-35931 AA predicted worse survival in stage III-IV treated with radiation (multiply adjusted hazard ratio (HR) 1.66, 95% confidence interval (CI) 1.15-2.40; HR over the first three follow-up years 1.92, 95% CI 1.28-2.88) and better survival in stage III-IV not treated with radiation (HR 0.26, 95% CI 0.11-0.62). Unassociated with survival in stage III-IV treated with radiation (HR 1.00, 95% CI 0.67-1.51), CCND1-870 GG predicted better survival in stage III-IV not treated with radiation (HR 0.14, 95% CI 0.04-0.50). Survival in stage I-II did not depend on ERCC2 A35931C or CCND1 G870A genotype.
Conclusions
Promoting tumor progression in untreated patients, germline differences in DNA repair or cell cycle control may improve treatment outcome in patients treated with DNA damaging agents.
Impact
ERCC2 A35931C may help distinguish advanced stage SCCHN with better outcomes from radiation treatment.
doi:10.1158/1055-9965.EPI-11-0520
PMCID: PMC3210907  PMID: 21890746
8.  XPF expression correlates with clinical outcome in squamous cell carcinoma of the head and neck 
Purpose
Tumor-specific biomarkers that predict resistance to DNA damaging agents may improve therapeutic outcomes by guiding the selection of effective therapies and limiting morbidity related to ineffective approaches. XPF (ERCC4) is an essential component of several DNA repair pathways and XPF-deficient cells are exquisitely sensitive to DNA damaging agents. The purpose of this study was to determine whether XPF expression levels predict clinical response to DNA damaging agents in head and neck squamous cell carcinoma (HNSCC).
Experimental Design
Quantitative immunohistochemistry was used to measure XPF expression in tumors from a cohort of 80 patients with newly diagnosed HNSCC treated with radiation therapy with or without platinum-based chemotherapy; samples were collected prospectively. Genomic DNA isolated from blood samples was analyzed for nine single nucleotide polymorphisms in the XPF gene using a custom array. The primary endpoint was progression-free survival (PFS).
Results
XPF expression was higher in tumors from the oral cavity than from the other sites (p<0.01). High XPF expression correlated with early time to progression both by univariate (HR =1.87, p=0.03) and multivariate analysis (HR =1.83, p=0.05). The one year PFS for high expressers was 47% (95% CI = 31% – 62%) compared to 72% (95% CI = 55% – 83%) for low expressers. In addition, we identified four XPF single nucleotide polymorphisms (SNPs) that demonstrated marginal association with treatment failure.
Conclusions
Expression level of XPF in HNSCC tumors correlates with clinical response to DNA damaging agents. XPF has potential to guide next-generation personalized cancer therapy.
doi:10.1158/1078-0432.CCR-11-0086
PMCID: PMC3156890  PMID: 21737503
XPF-ERCC1; DNA repair; SNP; platinum; biomarker
9.  The Mutational Landscape of Head and Neck Squamous Cell Carcinoma 
Science (New York, N.Y.)  2011;333(6046):1157-1160.
Head and neck squamous cell carcinoma (HNSCC) is a common, morbid, and frequently lethal malignancy. To uncover its mutational spectrum, we analyzed whole-exome sequencing data from 74 tumor-normal pairs. The majority exhibited a mutational profile consistent with tobacco exposure; human papilloma virus was detectable by sequencing of DNA from infected tumors. In addition to identifying previously known HNSCC genes (TP53, CDKN2A, PTEN, PIK3CA, and HRAS), the analysis revealed many genes not previously implicated in this malignancy. At least 30% of cases harbored mutations in genes that regulate squamous differentiation (e.g., NOTCH1, IRF6, and TP63), implicating its dysregulation as a major driver of HNSCC carcinogenesis. More generally, the results indicate the ability of large-scale sequencing to reveal fundamental tumorigenic mechanisms.
doi:10.1126/science.1208130
PMCID: PMC3415217  PMID: 21798893
10.  Genome-Wide Association Study of Survival in Non–Small Cell Lung Cancer Patients Receiving Platinum-Based Chemotherapy 
Background
Interindividual variation in genetic background may influence the response to chemotherapy and overall survival for patients with advanced-stage non–small cell lung cancer (NSCLC).
Methods
To identify genetic variants associated with poor overall survival in these patients, we conducted a genome-wide scan of 307 260 single-nucleotide polymorphisms (SNPs) in 327 advanced-stage NSCLC patients who received platinum-based chemotherapy with or without radiation at the University of Texas MD Anderson Cancer Center (the discovery population). A fast-track replication was performed for 315 patients from the Mayo Clinic followed by a second validation at the University of Pittsburgh in 420 patients enrolled in the Spanish Lung Cancer Group PLATAX clinical trial. A pooled analysis combining the Mayo Clinic and PLATAX populations or all three populations was also used to validate the results. We assessed the association of each SNP with overall survival by multivariable Cox proportional hazard regression analysis. All statistical tests were two-sided.
Results
SNP rs1878022 in the chemokine-like receptor 1 (CMKLR1) was statistically significantly associated with poor overall survival in the MD Anderson discovery population (hazard ratio [HR] of death = 1.59, 95% confidence interval [CI] = 1.32 to 1.92, P = 1.42 × 10−6), in the PLATAX clinical trial (HR of death = 1.23, 95% CI = 1.00 to 1.51, P = .05), in the pooled Mayo Clinic and PLATAX validation (HR of death = 1.22, 95% CI = 1.06 to 1.40, P = .005), and in pooled analysis of all three populations (HR of death = 1.33, 95% CI = 1.19 to 1.48, P = 5.13 × 10−7). Carrying a variant genotype of rs10937823 was associated with decreased overall survival (HR of death = 1.82, 95% CI = 1.42 to 2.33, P = 1.73 × 10−6) in the pooled MD Anderson and Mayo Clinic populations but not in the PLATAX trial patient population (HR of death = 0.96, 95% CI = 0.69 to 1.35).
Conclusion
These results have the potential to contribute to the future development of personalized chemotherapy treatments for individual NSCLC patients.
doi:10.1093/jnci/djr075
PMCID: PMC3096796  PMID: 21483023
11.  A sex-specific association between a 15q25 variant and upper aerodigestive tract cancers 
Background
Sequence variants located at 15q25 have been associated with lung cancer and propensity to smoke. We recently reported an association between rs16969968 and risk of upper aerodigestive tract (UADT) cancers (oral cavity, oropharynx, hypopharynx, larynx and esophagus) in women (odds ratio (OR) =1.24, P=0.003) with little effect in men (OR=1.04, P=0.35).
Methods
In a coordinated genotyping study within the International Head and Neck Cancer Epidemiology (INHANCE) consortium, we have sought to replicate these findings in an additional 4,604 cases and 6,239 controls from 10 independent UADT cancer case-control studies.
Results
rs16969968 was again associated with UADT cancers in women (OR=1.21, 95% confidence interval(CI)=1.08–1.36, P=0.001) and a similar lack of observed effect in men (OR=1.02, 95%CI=0.95–1.09, P=0.66) (P-heterogeneity=0.01). In a pooled analysis of the original and current studies, totaling 8,572 UADT cancer cases and 11,558 controls, the association was observed among females (OR=1.22, 95%CI=1.12–1.34, P=7×10−6) but not males (OR=1.02, 95%CI=0.97–1.08, P=0.35) (P-heterogeneity=6×10−4). There was little evidence for a sex difference in the association between this variant and cigarettes smoked per day, with male and female rs16969968 variant carriers smoking approximately the same amount more in the 11,991 ever smokers in the pooled analysis of the 14 studies (P-heterogeneity=0.86).
Conclusions
This study has confirmed a sex difference in the association between the 15q25 variant rs16969968 and UADT cancers.
Impact
Further research is warranted to elucidate the mechanisms underlying these observations.
doi:10.1158/1055-9965.EPI-10-1008
PMCID: PMC3070066  PMID: 21335511
genetic variants; 15q25; nicotinic acetylcholine receptor; upper aerodigestive tract cancers; cigarettes per day
12.  Phase II Trial of Pemetrexed and Bevacizumab in Patients With Recurrent or Metastatic Head and Neck Cancer 
Journal of Clinical Oncology  2011;29(9):1140-1145.
Purpose
We hypothesized that bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), will potentiate the activity of pemetrexed, a multitargeted antifolate, in squamous cell carcinoma of the head and neck (SCCHN).
Patients and Methods
Patients with previously untreated, recurrent, or metastatic SCCHN were treated with pemetrexed 500 mg/m2 and bevacizumab 15 mg/kg given intravenously every 21 days with folic acid and B12 supplementation until disease progression. Primary end point was time-to-progression (TTP). DNA was isolated from whole blood samples for the detection of polymorphisms in thymidylate synthase, methylenetetrahydrofolate reductase (MTHFR), and VEGF.
Results
Forty patients were enrolled. The median TTP was 5 months, and the median overall survival (OS) was 11.3 months. In 37 evaluable patients, the overall response rate was 30%, including a complete response rate of 5%, and the disease control rate was 86%. Grade 3 to 5 bleeding events occurred in six patients (15%): four were grade 3, and two were fatal. Other serious toxicities in 10% or more of patients included neutropenia (10%) and infection (12.5%). One patient died of sepsis after receiving eight cycles of therapy. For the MTHFR A1298C (rs1801131) single nucleotide polymorphisms, homozygote patients with AA had worse OS (P = .034).
Conclusion
The addition of bevacizumab to pemetrexed resulted in promising efficacy outcomes in SCCHN. Bleeding events were frequent but some may have been due to natural history of disease. Polymorphisms in MTHFR may offer potential for treatment individualization.
doi:10.1200/JCO.2010.33.3591
PMCID: PMC3083869  PMID: 21343546
13.  Correction: A Genome-Wide Association Study of Upper Aerodigestive Tract Cancers Conducted within the INHANCE Consortium 
McKay, James D. | Truong, Therese | Gaborieau, Valerie | Chabrier, Amelie | Chuang, Shu-Chun | Byrnes, Graham | Zaridze, David | Shangina, Oxana | Szeszenia-Dabrowska, Neonila | Lissowska, Jolanta | Rudnai, Peter | Fabianova, Eleonora | Bucur, Alexandru | Bencko, Vladimir | Holcatova, Ivana | Janout, Vladimir | Foretova, Lenka | Lagiou, Pagona | Trichopoulos, Dimitrios | Benhamou, Simone | Bouchardy, Christine | Ahrens, Wolfgang | Merletti, Franco | Richiardi, Lorenzo | Talamini, Renato | Barzan, Luigi | Kjaerheim, Kristina | Macfarlane, Gary J. | Macfarlane, Tatiana V. | Simonato, Lorenzo | Canova, Cristina | Agudo, Antonio | Castellsagué, Xavier | Lowry, Ray | Conway, David I. | McKinney, Patricia A. | Healy, Claire M. | Toner, Mary E. | Znaor, Ariana | Curado, Maria Paula | Koifman, Sergio | Menezes, Ana | Wünsch-Filho, Victor | Neto, José Eluf | Garrote, Leticia Fernández | Boccia, Stefania | Cadoni, Gabriella | Arzani, Dario | Olshan, Andrew F. | Weissler, Mark C. | Funkhouser, William K. | Luo, Jingchun | Lubiński, Jan | Trubicka, Joanna | Lener, Marcin | Oszutowska, Dorota | Schwartz, Stephen M. | Chen, Chu | Fish, Sherianne | Doody, David R. | Muscat, Joshua E. | Lazarus, Philip | Gallagher, Carla J. | Chang, Shen-Chih | Zhang, Zuo-Feng | Wei, Qingyi | Sturgis, Erich M. | Wang, Li-E | Franceschi, Silvia | Herrero, Rolando | Kelsey, Karl T. | McClean, Michael D. | Marsit, Carmen J. | Nelson, Heather H. | Romkes, Marjorie | Buch, Shama | Nukui, Tomoko | Zhong, Shilong | Lacko, Martin | Manni, Johannes J. | Peters, Wilbert H. M. | Hung, Rayjean J. | McLaughlin, John | Vatten, Lars | Njølstad, Inger | Goodman, Gary E. | Field, John K. | Liloglou, Triantafillos | Vineis, Paolo | Clavel-Chapelon, Francoise | Palli, Domenico | Tumino, Rosario | Krogh, Vittorio | Panico, Salvatore | González, Carlos A. | Quirós, J. Ramón | Martínez, Carmen | Navarro, Carmen | Ardanaz, Eva | Larrañaga, Nerea | Khaw, Kay-Tee | Key, Timothy | Bueno-de-Mesquita, H. Bas | Peeters, Petra H. M. | Trichopoulou, Antonia | Linseisen, Jakob | Boeing, Heiner | Hallmans, Göran | Overvad, Kim | Tjønneland, Anne | Kumle, Merethe | Riboli, Elio | Välk, Kristjan | Voodern, Tõnu | Metspalu, Andres | Zelenika, Diana | Boland, Anne | Delepine, Marc | Foglio, Mario | Lechner, Doris | Blanché, Hélène | Gut, Ivo G. | Galan, Pilar | Heath, Simon | Hashibe, Mia | Hayes, Richard B. | Boffetta, Paolo | Lathrop, Mark | Brennan, Paul
PLoS Genetics  2011;7(4):10.1371/annotation/9952526f-2f1f-47f3-af0f-1a7cf6f0abc1.
doi:10.1371/annotation/9952526f-2f1f-47f3-af0f-1a7cf6f0abc1
PMCID: PMC3084181
14.  A Genome-Wide Association Study of Upper Aerodigestive Tract Cancers Conducted within the INHANCE Consortium 
McKay, James D. | Truong, Therese | Gaborieau, Valerie | Chabrier, Amelie | Chuang, Shu-Chun | Byrnes, Graham | Zaridze, David | Shangina, Oxana | Szeszenia-Dabrowska, Neonila | Lissowska, Jolanta | Rudnai, Peter | Fabianova, Eleonora | Bucur, Alexandru | Bencko, Vladimir | Holcatova, Ivana | Janout, Vladimir | Foretova, Lenka | Lagiou, Pagona | Trichopoulos, Dimitrios | Benhamou, Simone | Bouchardy, Christine | Ahrens, Wolfgang | Merletti, Franco | Richiardi, Lorenzo | Talamini, Renato | Barzan, Luigi | Kjaerheim, Kristina | Macfarlane, Gary J. | Macfarlane, Tatiana V. | Simonato, Lorenzo | Canova, Cristina | Agudo, Antonio | Castellsagué, Xavier | Lowry, Ray | Conway, David I. | McKinney, Patricia A. | Healy, Claire M. | Toner, Mary E. | Znaor, Ariana | Curado, Maria Paula | Koifman, Sergio | Menezes, Ana | Wünsch-Filho, Victor | Neto, José Eluf | Garrote, Leticia Fernández | Boccia, Stefania | Cadoni, Gabriella | Arzani, Dario | Olshan, Andrew F. | Weissler, Mark C. | Funkhouser, William K. | Luo, Jingchun | Lubiński, Jan | Trubicka, Joanna | Lener, Marcin | Oszutowska, Dorota | Schwartz, Stephen M. | Chen, Chu | Fish, Sherianne | Doody, David R. | Muscat, Joshua E. | Lazarus, Philip | Gallagher, Carla J. | Chang, Shen-Chih | Zhang, Zuo-Feng | Wei, Qingyi | Sturgis, Erich M. | Wang, Li-E | Franceschi, Silvia | Herrero, Rolando | Kelsey, Karl T. | McClean, Michael D. | Marsit, Carmen J. | Nelson, Heather H. | Romkes, Marjorie | Buch, Shama | Nukui, Tomoko | Zhong, Shilong | Lacko, Martin | Manni, Johannes J. | Peters, Wilbert H. M. | Hung, Rayjean J. | McLaughlin, John | Vatten, Lars | Njølstad, Inger | Goodman, Gary E. | Field, John K. | Liloglou, Triantafillos | Vineis, Paolo | Clavel-Chapelon, Francoise | Palli, Domenico | Tumino, Rosario | Krogh, Vittorio | Panico, Salvatore | González, Carlos A. | Quirós, J. Ramón | Martínez, Carmen | Navarro, Carmen | Ardanaz, Eva | Larrañaga, Nerea | Khaw, Kay-Tee | Key, Timothy | Bueno-de-Mesquita, H. Bas | Peeters, Petra H. M. | Trichopoulou, Antonia | Linseisen, Jakob | Boeing, Heiner | Hallmans, Göran | Overvad, Kim | Tjønneland, Anne | Kumle, Merethe | Riboli, Elio | Välk, Kristjan | Voodern, Tõnu | Metspalu, Andres | Zelenika, Diana | Boland, Anne | Delepine, Marc | Foglio, Mario | Lechner, Doris | Blanché, Hélène | Gut, Ivo G. | Galan, Pilar | Heath, Simon | Hashibe, Mia | Hayes, Richard B. | Boffetta, Paolo | Lathrop, Mark | Brennan, Paul
PLoS Genetics  2011;7(3):e1001333.
Genome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in susceptibility to etiologically complex disease. We conducted a GWAS to identify common genetic variation involved in susceptibility to upper aero-digestive tract (UADT) cancers. Genome-wide genotyping was carried out using the Illumina HumanHap300 beadchips in 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls. The 19 top-ranked variants were investigated further in an additional 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies participating in the INHANCE consortium. Five common variants presented evidence for significant association in the combined analysis (p≤5×10−7). Two novel variants were identified, a 4q21 variant (rs1494961, p = 1×10−8) located near DNA repair related genes HEL308 and FAM175A (or Abraxas) and a 12q24 variant (rs4767364, p = 2×10−8) located in an extended linkage disequilibrium region that contains multiple genes including the aldehyde dehydrogenase 2 (ALDH2) gene. Three remaining variants are located in the ADH gene cluster and were identified previously in a candidate gene study involving some of these samples. The association between these three variants and UADT cancers was independently replicated in 5,092 UADT cancer cases and 6,794 controls non-overlapping samples presented here (rs1573496-ADH7, p = 5×10−8; rs1229984-ADH1B, p = 7×10−9; and rs698-ADH1C, p = 0.02). These results implicate two variants at 4q21 and 12q24 and further highlight three ADH variants in UADT cancer susceptibility.
Author Summary
We have used a two-phased study approach to identify common genetic variation involved in susceptibility to upper aero-digestive tract cancer. Using Illumina HumanHap300 beadchips, 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls, were genotyped for a panel 317,000 genetic variants that represent the majority of common genetic in the human genome. The 19 top-ranked variants were then studied in an additional series of 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies. Five variants were significantly associated with UADT cancer risk after the completion of both stages, including three residing within the alcohol dehydrogenase genes (ADH1B, ADH1C, ADH7) that have been previously described. Two additional variants were found, one near the ALDH2 gene and a second variant located in HEL308, a DNA repair gene. These results implicate two variants 4q21 and 12q24 and further highlight three ADH variants UADT cancer susceptibility.
doi:10.1371/journal.pgen.1001333
PMCID: PMC3060072  PMID: 21437268
15.  Smoking behavior one year after computed tomography (CT) screening for lung cancer: Effect of physician referral for abnormal CT findings 
Background
Computed tomography (CT) lung cancer screening offers a unique clinical setting in which to promote smoking cessation. Focusing on outcomes related to the reporting of CT abnormality, we examined the natural history of smoking in the Pittsburgh Lung Screening Study (PLuSS).
Methods
PLuSS recruited 50 to 79 year-old current and former cigarette smokers living in the Pittsburgh area. We examined self-reported smoking outcomes one year after study entry in a subgroup that contained n=2094 active cigarette smokers without interval lung cancer diagnosis (50.7% women, median age 57 years, 40 year median duration of cigarette smoking, and 65.2% ≥ 20 cigarettes per day). Analyses compared efforts to quit in relation to physician referral for abnormal CT.
Results
Since study entry, 58.5% (95% confidence interval (CI) 56.3%, 60.6%) reported any quit attempt and 27.2% (95% CI 25.3%, 29.1%) any quit interval longer than 30 days. One year after study entry, 15.5% (95% CI 14.0%, 17.1%) reported not smoking for more than 30 days. Comparing persons referred because of CT abnormalities creating moderate or high lung cancer suspicion (n=156; 7.4%) to persons not referred for any reason (n=1145; 54.7%), propensity score-adjusted fractions with any quit attempt and with any quit interval longer than 30 days increased 18.8% (95% CI 11.1%, 26.5%) and 17.7% (95% CI 9.4%, 26.0%), respectively. The fraction quit more than 30 days at one year increased 12.2% (95% CI 4.9%, 19.5%).
Conclusions
Persons who experienced referral because of abnormal CT reported more smoking cessation.
doi:10.1158/1055-9965.EPI-09-0895
PMCID: PMC2789354  PMID: 19959699
16.  The impact of genetic variation in DRD2 and SLC6A3 on smoking cessation in cohort of participants one year after enrollment in a lung cancer screening study 
Smoking cessation strategies continue to have disappointing results. By determining the interindividual genetic differences that influence smoking behaviors, we may be able to develop tailored strategies that increase the likelihood of successful cessation. This study attempts to determine genetic influences on the relationship between the dopamine pathway and smoking cessation by examining associations with a variable number tandem repeat variation in SLC6A3 and the DRD2 variants TaqIA (A2 vs. A1), TaqIB (B2 vs. B1), C957T (C vs. T), and -141C Ins/Del (C vs. Del). Baseline smokers in the Pittsburgh Lung Screening Study who provided information on smoking status one year later were evaluated. We frequency-matched those who were not abstinent at one year to those who were abstinent at one year by gender, decade of age, and time of enrollment (three month intervals) in a three to one ratio (N=881). Logistic regression was used to identify the effect of genotype on abstinence at one year. In a model containing the matching variables and other genotypes, DRD2 TaqIA was significantly associated with being abstinent at one year (p=0.01). Compared to participants who were homozygous TaqIA major allele (A2A2), participants who carried at least one minor allele (A1) were less likely to quit (Odds Ratio: 0.47, 95% CI: 0.24–0.94). The other dopamine receptor genotypes and the SLC6A3 genotype were not associated with smoking status at one-year. The association between DRD2 TaqIA and smoking cessation supports the hypothesis that genetic variation in the dopamine pathway influences smoking cessation.
doi:10.1002/ajmg.b.30801
PMCID: PMC2730224  PMID: 18563706
tobacco use cessation; genotype; case-control study; dopamine
17.  Exogenous and Endogenous Determinants of Blood Trihalomethane Levels after Showering 
Background
We previously conducted a study to assess whether household exposures to tap water increased an individual’s internal dose of trihalomethanes (THMs). Increases in blood THM levels among subjects who showered or bathed were variable, with increased levels tending to cluster in two groups.
Objectives
Our goal was to assess the importance of personal characteristics, previous exposures, genetic polymorphisms, and environmental exposures in determining THM concentrations in blood after showering.
Methods
One hundred study participants completed a health symptom questionnaire, a 48-hr food and water consumption diary, and took a 10-min shower in a controlled setting. We examined THM levels in blood samples collected at baseline and 10 and 30 min after the shower. We assessed the significance of personal characteristics, previous exposures to THMs, and specific gene polymorphisms in predicting postshower blood THM concentrations.
Results
We did not observe the clustering of blood THM concentrations observed in our earlier study. We found that environmental THM concentrations were important predictors of blood THM concentrations immediately after showering. For example, the chloroform concentration in the shower stall air was the most important predictor of blood chloroform levels 10 min after the shower (p < 0.001). Personal characteristics, previous exposures to THMs, and specific polymorphisms in CYP2D6 and GSTT1 genes were significant predictors of both baseline and postshowering blood THM concentrations as well as of changes in THM concentrations associated with showering.
Conclusion
The inclusion of information about individual physiologic characteristics and environmental measurements would be valuable in future studies to assess human health effects from exposures to THMs in tap water.
doi:10.1289/ehp.10049
PMCID: PMC2199304  PMID: 18197300
CYP2D6; CYP2E1; disinfection by-products; drinking water disinfection; GSTT1; showering exposures; trihalomethanes

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