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1.  Mapping of the IRF8 gene identifies a 3’ UTR variant associated with risk of chronic lymphocytic leukemia but not other common non-Hodgkin lymphoma subtypes 
Our genome-wide association study (GWAS) of chronic lymphocytic leukemia (CLL) identified 4 highly-correlated intronic variants within the IRF8 gene that were associated with CLL. These results were further supported by a recent meta-analysis of our GWAS with two other GWAS of CLL, supporting the IRF8 gene as a strong candidate for CLL risk.
To refine the genetic association of CLL risk, we performed Sanger sequencing of IRF8 in 94 CLL cases and 96 controls. We then performed fine-mapping by genotyping 39 variants (of which 10 were identified from sequencing) in 745 CLL cases and 1521 controls. We also assessed these associations with risk of other non-Hodgkin lymphoma (NHL) subtypes.
The strongest association with CLL risk was observed with a common SNP located within the 3’ UTR of IRF8 (rs1044873, log additive odds ratio = 0.7, P=1.81×10−6). This SNP was not associated with the other NHL subtypes (all P>0.05).
We provide evidence that rs1044873 in the IRF8 gene accounts for the initial GWAS signal for CLL risk. This association appears to be unique to CLL with little support for association with other common NHL subtypes. Future work is needed to assess functional role of IRF8 in CLL etiology.
These data provide support that a functional variant within the 3’ UTR of IRF8 may be driving the GWAS signal seen on 16q24.1 for CLL risk.
PMCID: PMC3596428  PMID: 23307532
CLL; NHL; SNPs; IRF8; risk locus
2.  Genome-wide Association Study Identifies Multiple Risk Loci for Chronic Lymphocytic Leukemia 
Berndt, Sonja I. | Skibola, Christine F. | Joseph, Vijai | Camp, Nicola J. | Nieters, Alexandra | Wang, Zhaoming | Cozen, Wendy | Monnereau, Alain | Wang, Sophia S. | Kelly, Rachel S. | Lan, Qing | Teras, Lauren R. | Chatterjee, Nilanjan | Chung, Charles C. | Yeager, Meredith | Brooks-Wilson, Angela R. | Hartge, Patricia | Purdue, Mark P. | Birmann, Brenda M. | Armstrong, Bruce K. | Cocco, Pierluigi | Zhang, Yawei | Severi, Gianluca | Zeleniuch-Jacquotte, Anne | Lawrence, Charles | Burdette, Laurie | Yuenger, Jeffrey | Hutchinson, Amy | Jacobs, Kevin B. | Call, Timothy G. | Shanafelt, Tait D. | Novak, Anne J. | Kay, Neil E. | Liebow, Mark | Wang, Alice H. | Smedby, Karin E | Adami, Hans-Olov | Melbye, Mads | Glimelius, Bengt | Chang, Ellen T. | Glenn, Martha | Curtin, Karen | Cannon-Albright, Lisa A. | Jones, Brandt | Diver, W. Ryan | Link, Brian K. | Weiner, George J. | Conde, Lucia | Bracci, Paige M. | Riby, Jacques | Holly, Elizabeth A. | Smith, Martyn T. | Jackson, Rebecca D. | Tinker, Lesley F. | Benavente, Yolanda | Becker, Nikolaus | Boffetta, Paolo | Brennan, Paul | Foretova, Lenka | Maynadie, Marc | McKay, James | Staines, Anthony | Rabe, Kari G. | Achenbach, Sara J. | Vachon, Celine M. | Goldin, Lynn R | Strom, Sara S. | Lanasa, Mark C. | Spector, Logan G. | Leis, Jose F. | Cunningham, Julie M. | Weinberg, J. Brice | Morrison, Vicki A. | Caporaso, Neil E. | Norman, Aaron D. | Linet, Martha S. | De Roos, Anneclaire J. | Morton, Lindsay M. | Severson, Richard K. | Riboli, Elio | Vineis, Paolo | Kaaks, Rudolph | Trichopoulos, Dimitrios | Masala, Giovanna | Weiderpass, Elisabete | Chirlaque, María-Dolores | Vermeulen, Roel C H | Travis, Ruth C. | Giles, Graham G. | Albanes, Demetrius | Virtamo, Jarmo | Weinstein, Stephanie | Clavel, Jacqueline | Zheng, Tongzhang | Holford, Theodore R | Offit, Kenneth | Zelenetz, Andrew | Klein, Robert J. | Spinelli, John J. | Bertrand, Kimberly A. | Laden, Francine | Giovannucci, Edward | Kraft, Peter | Kricker, Anne | Turner, Jenny | Vajdic, Claire M. | Ennas, Maria Grazia | Ferri, Giovanni M. | Miligi, Lucia | Liang, Liming | Sampson, Joshua | Crouch, Simon | Park, Ju-hyun | North, Kari E. | Cox, Angela | Snowden, John A. | Wright, Josh | Carracedo, Angel | Lopez-Otin, Carlos | Bea, Silvia | Salaverria, Itziar | Martin, David | Campo, Elias | Fraumeni, Joseph F. | de Sanjose, Silvia | Hjalgrim, Henrik | Cerhan, James R. | Chanock, Stephen J. | Rothman, Nathaniel | Slager, Susan L.
Nature genetics  2013;45(8):868-876.
PMCID: PMC3729927  PMID: 23770605
3.  Immnuophenotypic and Gene Expression Analysis of Monoclonal B Cell Lymphocytosis Shows Biologic Characteristics Associated With Good Prognosis CLL 
Monoclonal B cell lymphocytosis (MBL) is a hematologic condition wherein small B cell clones can be detected in the blood of asymptomatic individuals. Most MBL have an immunophenotype similar to chronic lymphocytic leukemia (CLL), and “CLL-like” MBL is a precursor to CLL. We used flow cytometry to identify MBL from unaffected members of CLL kindreds. We identified 101 MBL cases from 622 study subjects; of these, 82 individuals with MBL were further characterized. Ninety-one unique MBL clones were detected: 73 CLL-like MBL (CD5+CD20dimsIgdim), 11 atypical MBL (CD5+CD20+sIg+), and 7 CD5neg MBL (CD5negCD20+sIgneg). Extended immunophenotypic characterization of these MBL subtypes was performed, and significant differences in cell surface expression of CD23, CD49d, CD79b, and FMC-7 were observed among the groups. Markers of risk in CLL such as CD38, ZAP70, and CD49d were infrequently expressed in CLL-like MBL, but were expressed in the majority of atypical MBL. Interphase cytogenetics was performed in 35 MBL cases, and del 13q14 was most common (22/30 CLL-like MBL cases). Gene expression analysis using oligonucleotide arrays was performed on 7 CLL-like MBL, and showed activation of B cell receptor associated pathways. Our findings underscore the diversity of MBL subtypes and further clarify the relationship between MBL and other lymphoproliferative disorders.
PMCID: PMC3164475  PMID: 21617698
4.  Common Occurrence of Monoclonal B-cell Lymphocytosis Among Members of High-Risk CLL Families 
British journal of haematology  2010;151(2):152-158.
Monoclonal B-cell lymphocytosis (MBL) is an asymptomatic haematological condition characterized by low absolute levels of B-cell clones with a surface immunophenotype similar to that of chronic lymphocytic leukaemia (CLL). In the general population, MBL increases with age with a prevalence of 5–9% in individuals over age 60 years. It has been reported to be higher among first-degree relatives from CLL families. We report results of multi-parameter flow cytometry among 505 first-degree relatives with no personal history of lymphoproliferative disease from 140 families having at least two cases of CLL. Seventeen percent of relatives had MBL. Age was the most important determinant where the probability for developing MBL by age 90 years was 61%. MBL clustered in certain families but clustering was independent of the number of known CLL cases in a family. As is the case with CLL, males had a significantly higher risk for MBL than did females (p=0.04). MBL patients had significantly higher mean absolute lymphocyte counts (2.4 × 109/l) and B-cell counts (0.53 × 109/l) than those with a normal B-cell immunophenotype. Our findings show that MBL occurs at a very high rate in high risk CLL families. Both the age and gender distribution of MBL are parallel to CLL, implying a shared inherited risk.
PMCID: PMC2966536  PMID: 20738309
chronic lymphocytic leukaemia; high risk families; monoclonal B-cell lymphocytosis; flow cytometry
5.  Genetic susceptibility variants for chronic lymphocytic leukemia 
There is strong and consistent evidence that a genetic component contributes to the etiology of chronic lymphocytic leukemia (CLL). A recent genome-wide association study (GWAS) of CLL identified 7 genetic variants that increased the risk of CLL within a European population.
We evaluated the association of these variants, or variants in linkage disequilibrium (LD) with these variants, with CLL risk in an independent sample of 438 CLL cases and 328 controls.
Of these 7 SNPs, 6 had p-trend < 0.05 and had estimated odds ratios (ORs) that were strikingly comparable to those of the previous study. Associations were seen for rs9378805 (OR = 1.47, 95% CI: 1.19, 1.80, p-trend = 0.0003) near IRF4 and rs735665 near GRAMD1B (OR= 1.47; 95% CI: 1.14, 1.89; p-trend = 0.003). However, no associations (P> 0.05) were found for rs11083846, nor were any found for any SNPs in LD with rs11083846.
Our results confirm the previous findings and further support the role of a genetic basis in the etiology of CLL; however, more research is needed to elucidate the causal SNP(s) and the potential manner in which these SNPs or linked SNPs function in CLL pathogenesis.
PMCID: PMC2852480  PMID: 20332261
IRF4; CLL; genetic association
6.  Genome-wide association study of follicular lymphoma identifies a risk locus at 6p21.32 
Nature genetics  2010;42(8):661-664.
To identify susceptibility loci for non-Hodgkin lymphoma (NHL) subtypes, we conducted a three-stage genome-wide association study. We identified two variants associated with follicular lymphoma (FL) in 1,465 FL cases/6,958 controls at 6p21.32 (rs10484561, rs7755224, r2=1.0; combined p-values=1.12×10-29, 2.00×10-19), providing further support that MHC genetic variation influences FL susceptibility. Confirmatory evidence of a previously reported association was also found between chronic lymphocytic leukemia/small lymphocytic lymphoma and rs735665 (combined p-value=4.24×10-9).
PMCID: PMC2913472  PMID: 20639881
7.  Time to Smoke First Morning Cigarette and Lung Cancer in a Case–Control Study 
Targeting smokers at higher lung cancer risk can improve efficiency and reduce false-positive detection in lung cancer screening. We evaluated whether time to first cigarette after waking (TTFC), a single-item measure of nicotine dependency, could improve stratification of lung cancer risk beyond standard smoking metrics (intensity, duration, and pack-years).
In 3249 ever-smokers (n = 1812 case subjects; n = 1437 control subjects) from a population-based case–control study in Italy, we examined the association between TTFC and lung cancer using logistic regression and estimated lung cancer incidence by levels of TTFC, and intensity, duration, and pack-years using absolute risk regression. Significance tests were two-sided.
Compared with smokers with TTFC greater than 60 minutes, the lung cancer odds ratios for TTFC of 31 to 60 minutes, 6 to 30 minutes, and 5 or fewer minutes (by increasing dependency) were 2.57 (95% confidence interval [CI] = 2.03 to 3.26), 2.27 (95% CI = 1.79 to 2.88), and 3.50 (95% CI = 2.64 to 4.64), respectively (P trend < .0001). The average lung cancer incidence rates for smokers of 1 to 10, 11 to 20, 21 to 30 and more than 30 cigarettes per day were consistently higher among smokers with TTFC of 60 or fewer minutes vs more than 60 minutes (64.1 vs 11.7; 125.6 vs 28.6; 130.1 vs 40.7; and 260.8 vs 108.9 per 100000 person-years, respectively). The slopes of increase in lung cancer rates with smoking duration and pack-years were statistically significantly greater among smokers with higher dependency (P interaction < .001).
Lung cancer risk increases with shorter TTFC; this simple nicotine dependency measure increases lung cancer risk stratification beyond standard smoking measures. Assessing TTFC may improve lung cancer risk prediction and could be useful in lung cancer screening and smoking cessation programs.
PMCID: PMC4072901  PMID: 24948709
8.  Use of Multiple Imputation to Correct for Bias in Lung Cancer Incidence Trends by Histologic Subtype 
Over the past several decades, advances in lung cancer research and practice have led to refinements of histological diagnosis of lung cancer. The differential use and subsequent alterations of non-specific morphology codes, however, may have caused artifactual fluctuations in the incidence rates for histologic subtypes, thus biasing temporal trends.
We developed a multiple imputation (MI) method to correct lung cancer incidence for non-specific histology using data from the Surveillance, Epidemiology, and End Results (SEER) Program during 1975–2010.
For adenocarcinoma in men and squamous in both genders, the change to a increasing trend around 2005, after more than ten years of decreasing incidence, is apparently an artifact of the changes in histopathology practice and coding system. After imputation, the rates remained decreasing for adenocarcinoma and squamous in men, and became constant for squamous in women.
As molecular features of distinct histologies are increasingly identified by new technologies, accurate histological distinctions are becoming increasingly relevant to more effective 'targeted' therapies, and therefore, are important to track in patients. However, without incorporating the coding changes, the incidence trends estimated for histologic subtypes could be misleading.
The MI approach provides a valuable tool for bridging the different histology definitions, thus permitting meaningful inferences about the long-term trends of lung cancer by histological subtype.
PMCID: PMC4119525  PMID: 24855099
SEER; ICD-O-3; Non-specific morphology codes; Missing data; Ridge-penalized logistic regression
9.  Telomere length in white blood cell DNA and lung cancer: a pooled analysis of three prospective cohorts 
Cancer research  2014;74(15):4090-4098.
We investigated the relationship between telomere length and lung cancer in a pooled analysis from three prospective cohort studies: the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, conducted among men and women in the United States, and previously published data from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) trial conducted among male smokers in Finland, and the Shanghai Women's Health Study (SWHS), which is comprised primarily of never-smokers. The pooled population included 847 cases and 847 controls matched by study, age, and sex. Leukocyte telomere length was measured by a monochrome multiplex quantitative PCR assay. We used conditional logistic regression models to calculate odds ratios (OR) and their 95% confidence intervals (CI) for the association between telomere length and lung cancer risk, adjusted for age and pack-years of smoking. Longer telomere length was associated with increased lung cancer risk in the pooled analysis (OR(95% CI) by quartile: 1.00; 1.24(0.90–1.71); 1.27(0.91–1.78); and 1.86(1.33–2.62); P-trend=0.000022). Findings were consistent across the three cohorts and strongest for subjects with very long telomere length, i.e., lung cancer risks for telomere length (OR(95% CI)) in the upper half of the fourth quartile were 2.41(1.28–4.52), 2.16(1.11–4.23) and 3.02(1.39–6.58) for the PLCO trial, the ATBC trial, and the SWHS, respectively. In addition, the association persisted among cases diagnosed more than six years after blood collection and was particularly evident for female adenocarcinoma cases. Telomere length in white blood cell DNA may be a biomarker of future increased risk of lung cancer in diverse populations.
PMCID: PMC4119534  PMID: 24853549
Leukocytes; Lung cancer; Prospective; Telomeres
10.  Metabolites of tobacco smoking and colorectal cancer risk 
Carcinogenesis  2014;35(7):1516-1522.
Epidemiologic studies report inconsistent and modest associations between smoking and colorectal cancer. Serum hydroxycotinine captures smoking behavior and metabolic variation, and is associated with a 2.7-fold increased risk of incident colorectal cancer, supporting a role for tobacco in this malignancy.
Colorectal cancer is not strictly considered a tobacco-related malignancy, but modest associations have emerged from large meta-analyses. Most studies, however, use self-reported data, which are subject to misclassification. Biomarkers of tobacco exposure may reduce misclassification and provide insight into metabolic variability that potentially influences carcinogenesis. Our aim was to identify metabolites that represent smoking habits and individual variation in tobacco metabolism, and investigate their association with colorectal cancer. In a nested case-control study of 255 colorectal cancers and 254 matched controls identified in the Prostate, Lung, Colorectal and Ovarian cancer screening trial, baseline serum was used to identify metabolites by ultra-high-performance liquid-phase chromatography and mass spectrometry, as well as gas chromatography with tandem mass spectrometry. Odds ratios (OR) and 95% confidence intervals (CI) were estimated by logistic regression. Self-reported current smoking was associated with serum cotinine, O-cresol sulfate and hydroxycotinine. Self-reported current smoking of any tobacco (OR = 1.90, 95% CI: 1.02–3.54) and current cigarette smoking (OR = 1.51, 95% CI: 0.75–3.04) were associated with elevated colorectal cancer risks, although the latter was not statistically significant. Individuals with detectable levels of hydroxycotinine had an increased colorectal cancer risk compared with those with undetectable levels (OR = 2.68, 95% CI: 1.33–5.40). Although those with detectable levels of cotinine had a suggestive elevated risk of this malignancy (OR = 1.81, 95% CI: 0.98–3.33), those with detectable levels of O-cresol sulfate did not (OR = 1.16, 95% CI: 0.57–2.37). Biomarkers capturing smoking behavior and metabolic variation exhibit stronger associations with colorectal cancer than self-report, providing additional evidence for a role for tobacco in this malignancy.
PMCID: PMC4076812  PMID: 24648381
11.  Lung cancer risk among bricklayers in a pooled analysis of case–control studies 
Bricklayers may be exposed to several lung carcinogens, including crystalline silica and asbestos. Previous studies that analyzed lung cancer risk among these workers had several study design limitations. We examined lung cancer risk among bricklayers within SYNERGY, a large international pooled analysis of case–control studies on lung cancer and the joint effects of occupational carcinogens. For men ever employed as bricklayers we estimated odds ratios (OR) and 95% confidence intervals (CI) adjusted for study center, age, lifetime smoking history and employment in occupations with exposures to known or suspected lung carcinogens. Among 15,608 cases and 18,531 controls, there were 695 cases and 469 controls who had ever worked as bricklayers (OR: 1.47; 95% CI: 1.28–1.68). In studies using population controls the OR was 1.55 (95% CI: 1.32–1.81, 540/349 cases/controls), while it was 1.24 (95% CI: 0.93–1.64, 155/120 cases/controls) in hospital-based studies. There was a clear positive trend with length of employment (p < 0.001). The relative risk was higher for squamous (OR: 1.68, 95% CI: 1.42–1.98, 309 cases) and small cell carcinomas (OR: 1.78, 95% CI: 1.44–2.20, 140 cases), than for adenocarcinoma (OR: 1.17, 95% CI: 0.95–1.43, 150 cases) (p-homogeneity: 0.0007). ORs were still elevated after additional adjustment for education and in analyses using blue collar workers as referents. This study provided robust evidence of increased lung cancer risk in bricklayers. Although non-causal explanations cannot be completely ruled out, the association is plausible in view of the potential for exposure to several carcinogens, notably crystalline silica and to a lesser extent asbestos.
What's new?
In their work, bricklayers can be exposed to various airborne carcinogens, including crystalline silica and asbestos. Previous studies of cancer risk have not accounted for full employment history or smoking status, and failed to establish a firm relationship between bricklaying and lung cancer. In this study, the authors used data from the largest collection of case-control studies on lung cancer with complete occupational and smoking history existing today, the SYNERGY project. They found clear evidence that lung cancer risk increases in proportion to the length of time spent working as a bricklayer, paving the way for better protection and compensation for those in this occupation.
PMCID: PMC4477910  PMID: 24861979
lung neoplasms; case–control studies; bricklayers; occupational health; epidemiology
12.  HPV-associated lung cancers: an international pooled analysis 
Carcinogenesis  2014;35(6):1267-1275.
Human papillomavirus (HPV) is the etiologic risk factor for cervical cancer. Some studies have suggested an association with a subset of lung tumors, but the etiologic link has not been firmly established. We performed an international pooled analysis of cross-sectional studies (27 datasets, n = 3249 patients) to evaluate HPV DNA prevalence in lung cancer and to investigate viral presence according to clinical and demographic characteristics. HPV16/18 were the most commonly detected, but with substantial variation in viral prevalence between geographic regions. The highest prevalence of HPV16/18 was observed in South and Central America, followed by Asia, North America and Europe (adjusted prevalence rates = 22, 5, 4 and 3%, respectively). Higher HPV16 prevalence was noted in each geographic region compared with HPV18, except in North America. HPV16/18-positive lung cancer was less likely observed among White race (adjusted odds ratio [OR] = 0.33, 95% confidence interval [CI] = 0.12–0.90), whereas no associations were observed with gender, smoking history, age, histology or stage. Comparisons between tumor and normal lung tissue show that HPV was more likely to be present in lung cancer rather than normal lung tissues (OR = 3.86, 95% CI = 2.87–5.19). Among a subset of patients with HPV16-positive tumors, integration was primarily among female patients (93%, 13/14), while the physical status in male cases (N = 14) was inconsistent. Our findings confirm that HPV DNA is present in a small fraction of lung tumors, with large geographic variations. Further comprehensive analysis is needed to assess whether this association reflects a causal relationship.
PMCID: PMC4043241  PMID: 24523449
13.  Time to First Morning Cigarette and Risk of Chronic Obstructive Pulmonary Disease: Smokers in the PLCO Cancer Screening Trial 
PLoS ONE  2015;10(5):e0125973.
Time to first cigarette (TTFC) after waking is an indicator of nicotine dependence. The association between TTFC and chronic obstructive pulmonary disease (COPD), the third leading cause of death in the United States, has not yet been reported.
We investigated the cross-sectional association between TTFC and prevalent COPD among 6,108 current smokers in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. COPD was defined as a self-reported diagnosis of emphysema, chronic bronchitis, or both. Current smokers in PLCO reported TTFC, the amount of time they typically waited before smoking their first cigarette of the day after waking, in four categories: ≤5, 6-30, 31-60, or >60 minutes. We used logistic regression models to investigate the association between TTFC and prevalent COPD with adjustments for age, gender, race, education, and smoking (cigarettes/day, years smoked during lifetime, pack-years, age at smoking initiation), and prior lung cancer diagnosis.
COPD was reported by 19% of these 6,108 smokers. Individuals with the shortest TTFC had the greatest risk of COPD; compared to those with the longest TTFC (>60 minutes) the adjusted odds ratios (OR) and 95% confidence intervals (CI) for COPD were 1.48 (95% CI, 1.15-1.91), 1.64 (95% CI, 1.29-2.08), 2.18 (95% CI, 1.65-2.87) for those with TTFC 31-60 minutes, 6-30 minutes, and ≤5 minutes, respectively (P-trend <0.0001). The association between TTFC and emphysema was similar to that for bronchitis, albeit the ORs were slightly stronger for chronic bronchitis; comparing TTFC ≤5 minutes to >60 minutes, the adjusted OR (95% CI) was 2.29 (1.69-3.12) for emphysema and 2.99 (1.95-4.59) for chronic bronchitis.
Current smokers with shorter TTFC have increased risk of COPD compared to those with longer TTFC, even after comprehensive adjustment for established smoking covariates. Future epidemiologic studies, including prospective designs, should incorporate TTFC to better assess disease risk and evaluate the potential utility of TTFC as a COPD screening tool for smokers in the clinical setting.
PMCID: PMC4436174  PMID: 25985429
14.  The 19q12 bladder cancer GWAS signal: association with cyclin E function and aggressive disease 
Fu, Yi-Ping | Kohaar, Indu | Moore, Lee E. | Lenz, Petra | Figueroa, Jonine D. | Tang, Wei | Porter-Gill, Patricia | Chatterjee, Nilanjan | Scott-Johnson, Alexandra | Garcia-Closas, Montserrat | Muchmore, Brian | Baris, Dalsu | Paquin, Ashley | Ylaya, Kris | Schwenn, Molly | Apolo, Andrea B. | Karagas, Margaret R. | Tarway, McAnthony | Johnson, Alison | Mumy, Adam | Schned, Alan | Guedez, Liliana | Jones, Michael A. | Kida, Masatoshi | Monawar Hosain, GM | Malats, Nuria | Kogevinas, Manolis | Tardon, Adonina | Serra, Consol | Carrato, Alfredo | Garcia-Closas, Reina | Lloreta, Josep | Wu, Xifeng | Purdue, Mark | Andriole, Gerald L. | Grubb, Robert L. | Black, Amanda | Landi, Maria T. | Caporaso, Neil E. | Vineis, Paolo | Siddiq, Afshan | Bueno-de-Mesquita, H. Bas | Trichopoulos, Dimitrios | Ljungberg, Börje | Severi, Gianluca | Weiderpass, Elisabete | Krogh, Vittorio | Dorronsoro, Miren | Travis, Ruth C. | Tjønneland, Anne | Brennan, Paul | Chang-Claude, Jenny | Riboli, Elio | Prescott, Jennifer | Chen, Constance | De Vivo, Immaculata | Govannucci, Edward | Hunter, David | Kraft, Peter | Lindstrom, Sara | Gapstur, Susan M. | Jacobs, Eric J. | Diver, W. Ryan | Albanes, Demetrius | Weinstein, Stephanie J. | Virtamo, Jarmo | Kooperberg, Charles | Hohensee, Chancellor | Rodabough, Rebecca J. | Cortessis, Victoria K. | Conti, David V. | Gago-Dominguez, Manuela | Stern, Mariana C. | Pike, Malcolm C. | Van Den Berg, David | Yuan, Jian-Min | Haiman, Christopher A. | Cussenot, Olivier | Cancel-Tassin, Geraldine | Roupret, Morgan | Comperat, Eva | Porru, Stefano | Carta, Angela | Pavanello, Sofia | Arici, Cecilia | Mastrangelo, Giuseppe | Grossman, H. Barton | Wang, Zhaoming | Deng, Xiang | Chung, Charles C. | Hutchinson, Amy | Burdette, Laurie | Wheeler, William | Fraumeni, Joseph | Chanock, Stephen J. | Hewitt, Stephen M. | Silverman, Debra T. | Rothman, Nathaniel | Prokunina-Olsson, Ludmila
Cancer research  2014;74(20):5808-5818.
A genome-wide association study (GWAS) of bladder cancer identified a genetic marker rs8102137 within the 19q12 region as a novel susceptibility variant. This marker is located upstream of the CCNE1 gene, which encodes cyclin E, a cell cycle protein. We performed genetic fine mapping analysis of the CCNE1 region using data from two bladder cancer GWAS (5,942 cases and 10,857 controls). We found that the original GWAS marker rs8102137 represents a group of 47 linked SNPs (with r2≥0.7) associated with increased bladder cancer risk. From this group we selected a functional promoter variant rs7257330, which showed strong allele-specific binding of nuclear proteins in several cell lines. In both GWAS, rs7257330 was associated only with aggressive bladder cancer, with a combined per-allele odds ratio (OR) =1.18 (95%CI=1.09-1.27, p=4.67×10−5 vs. OR =1.01 (95%CI=0.93-1.10, p=0.79) for non-aggressive disease, with p=0.0015 for case-only analysis. Cyclin E protein expression analyzed in 265 bladder tumors was increased in aggressive tumors (p=0.013) and, independently, with each rs7257330-A risk allele (ptrend=0.024). Over-expression of recombinant cyclin E in cell lines caused significant acceleration of cell cycle. In conclusion, we defined the 19q12 signal as the first GWAS signal specific for aggressive bladder cancer. Molecular mechanisms of this genetic association may be related to cyclin E over-expression and alteration of cell cycle in carriers of CCNE1 risk variants. In combination with established bladder cancer risk factors and other somatic and germline genetic markers, the CCNE1 variants could be useful for inclusion into bladder cancer risk prediction models.
PMCID: PMC4203382  PMID: 25320178
Aggressive bladder cancer; cyclin E; cell cycle; single nucleotide polymorphism; GWAS
15.  Genome-wide association study identifies multiple susceptibility loci for pancreatic cancer 
Wolpin, Brian M. | Rizzato, Cosmeri | Kraft, Peter | Kooperberg, Charles | Petersen, Gloria M. | Wang, Zhaoming | Arslan, Alan A. | Beane-Freeman, Laura | Bracci, Paige M. | Buring, Julie | Canzian, Federico | Duell, Eric J. | Gallinger, Steven | Giles, Graham G. | Goodman, Gary E. | Goodman, Phyllis J. | Jacobs, Eric J. | Kamineni, Aruna | Klein, Alison P. | Kolonel, Laurence N. | Kulke, Matthew H. | Li, Donghui | Malats, Núria | Olson, Sara H. | Risch, Harvey A. | Sesso, Howard D. | Visvanathan, Kala | White, Emily | Zheng, Wei | Abnet, Christian C. | Albanes, Demetrius | Andreotti, Gabriella | Austin, Melissa A. | Barfield, Richard | Basso, Daniela | Berndt, Sonja I. | Boutron-Ruault, Marie-Christine | Brotzman, Michelle | Büchler, Markus W. | Bueno-de-Mesquita, H. Bas | Bugert, Peter | Burdette, Laurie | Campa, Daniele | Caporaso, Neil E. | Capurso, Gabriele | Chung, Charles | Cotterchio, Michelle | Costello, Eithne | Elena, Joanne | Funel, Niccola | Gaziano, J. Michael | Giese, Nathalia A. | Giovannucci, Edward L. | Goggins, Michael | Gorman, Megan J. | Gross, Myron | Haiman, Christopher A. | Hassan, Manal | Helzlsouer, Kathy J. | Henderson, Brian E. | Holly, Elizabeth A. | Hu, Nan | Hunter, David J. | Innocenti, Federico | Jenab, Mazda | Kaaks, Rudolf | Key, Timothy J. | Khaw, Kay-Tee | Klein, Eric A. | Kogevinas, Manolis | Krogh, Vittorio | Kupcinskas, Juozas | Kurtz, Robert C. | LaCroix, Andrea | Landi, Maria T. | Landi, Stefano | Le Marchand, Loic | Mambrini, Andrea | Mannisto, Satu | Milne, Roger L. | Nakamura, Yusuke | Oberg, Ann L. | Owzar, Kouros | Patel, Alpa V. | Peeters, Petra H. M. | Peters, Ulrike | Pezzilli, Raffaele | Piepoli, Ada | Porta, Miquel | Real, Francisco X. | Riboli, Elio | Rothman, Nathaniel | Scarpa, Aldo | Shu, Xiao-Ou | Silverman, Debra T. | Soucek, Pavel | Sund, Malin | Talar-Wojnarowska, Renata | Taylor, Philip R. | Theodoropoulos, George E. | Thornquist, Mark | Tjønneland, Anne | Tobias, Geoffrey S. | Trichopoulos, Dimitrios | Vodicka, Pavel | Wactawski-Wende, Jean | Wentzensen, Nicolas | Wu, Chen | Yu, Herbert | Yu, Kai | Zeleniuch-Jacquotte, Anne | Hoover, Robert | Hartge, Patricia | Fuchs, Charles | Chanock, Stephen J. | Stolzenberg-Solomon, Rachael S. | Amundadottir, Laufey T.
Nature genetics  2014;46(9):994-1000.
We performed a multistage genome-wide association study (GWAS) including 7,683 individuals with pancreatic cancer and 14,397 controls of European descent. Four new loci reached genome-wide significance: rs6971499 at 7q32.3 (LINC-PINT; per-allele odds ratio [OR] = 0.79; 95% confidence interval [CI] = 0.74–0.84; P = 3.0×10−12), rs7190458 at 16q23.1 (BCAR1/CTRB1/CTRB2; OR = 1.46; 95% CI = 1.30–1.65; P = 1.1×10−10), rs9581943 at 13q12.2 (PDX1; OR = 1.15; 95% CI = 1.10–1.20; P = 2.4×10−9), and rs16986825 at 22q12.1 (ZNRF3; OR = 1.18; 95% CI = 1.12–1.25; P = 1.2×10−8). An independent signal was identified in exon 2 of TERT at the established region 5p15.33 (rs2736098; OR = 0.80; 95% CI = 0.76–0.85; P = 9.8×10−14). We also identified a locus at 8q24.21 (rs1561927; P = 1.3×10−7) that approached genome-wide significance located 455 kb telomeric of PVT1. Our study has identified multiple new susceptibility alleles for pancreatic cancer worthy of follow-up studies.
PMCID: PMC4191666  PMID: 25086665
16.  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.
PMCID: PMC4074058  PMID: 24880342
17.  Circulating Inflammation Markers and Prospective Risk for Lung Cancer 
Despite growing recognition of an etiologic role for inflammation in lung carcinogenesis, few prospective epidemiologic studies have comprehensively investigated the association of circulating inflammation markers with lung cancer.
We conducted a nested case–control study (n = 526 lung cancer patients and n = 592 control subjects) within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Control subjects were matched to lung cancer case patients on age, sex, follow-up time (median = 2.9 years), randomization year, and smoking (pack-years and time since quitting). Serum levels of 77 inflammation markers were measured using a Luminex bead-based assay. Conditional logistic regression and weighted Cox models were used to estimate odds ratios (ORs) and cumulative risks, respectively.
Of 68 evaluable markers, 11 were statistically significantly associated with lung cancer risk (P trend across marker categories < .05), including acute-phase proteins (C-reactive protein [CRP], serum amyloid A [SAA]), proinflammatory cytokines (soluble tumor necrosis factor receptor 2 [sTNFRII]), anti-inflammatory cytokines (interleukin 1 receptor antagonist [IL-1RA]), lymphoid differentiation cytokines (interleukin 7 [IL-7]), growth factors (transforming growth factor alpha [TGF-A]), and chemokines (epithelial neutrophil-activating peptide 78 [ENA 78/CXCL5], monokine induced by gamma interferon [MIG/CXCL9], B cell–attracting chemokine 1 [BCA-1/CXCL13], thymus activation regulated chemokine [TARC/CCL17], macrophage-derived chemokine [MDC/CCL22]). Elevated marker levels were associated with increased lung cancer risk, with odds ratios comparing the highest vs the lowest group ranging from 1.47 (IL-7) to 2.27 (CRP). For IL-1RA, elevated levels were associated with decreased lung cancer risk (OR = 0.71; 95% confidence interval = 0.51 to 1.00). Associations did not differ by smoking, lung cancer histology, or latency. A cross-validated inflammation score using four independent markers (CRP, BCA-1/CXCL13, MDC/CCL22, and IL-1RA) provided good separation in 10-year lung cancer cumulative risks among former smokers (quartile [Q] 1 = 1.1% vs Q4 = 3.1%) and current smokers (Q1 = 2.3% vs Q4 = 7.9%) even after adjustment for smoking.
Some circulating inflammation marker levels are associated with prospective lung cancer risk.
PMCID: PMC3888091  PMID: 24249745
20.  Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma 
Nature genetics  2014;46(5):482-486.
Although CDKN2A is the most frequent high-risk melanoma susceptibility gene, the underlying genetic factors for most melanoma-prone families remain unknown. Using whole exome sequencing, we identified a rare variant that arose as a founder mutation in the telomere shelterin POT1 gene (g.7:124493086 C>T, Ser270Asn) in five unrelated melanoma-prone families from Romagna, Italy. Carriers of this variant had increased telomere length and elevated fragile telomeres suggesting that this variant perturbs telomere maintenance. Two additional rare POT1 variants were identified in all cases sequenced in two other Italian families, yielding a frequency of POT1 variants comparable to that of CDKN2A mutations in this population. These variants were not found in public databases or in 2,038 genotyped Italian controls. We also identified two rare recurrent POT1 variants in American and French familial melanoma cases. Our findings suggest that POT1 is a major susceptibility gene for familial melanoma in several populations.
PMCID: PMC4056593  PMID: 24686846
21.  Maximizing DNA Yield for Epidemiologic Studies: No More Buffy Coats? 
American Journal of Epidemiology  2013;178(7):1170-1176.
Some molecular analyses require microgram quantities of DNA, yet many epidemiologic studies preserve only the buffy coat. In Frederick, Maryland, in 2010, we estimated DNA yields from 5 mL of whole blood and from equivalent amounts of all-cell-pellet (ACP) fraction, buffy coat, and residual blood cells from fresh blood (n = 10 volunteers) and from both fresh and frozen blood (n = 10). We extracted DNA with the QIAamp DNA Blood Midi Kit (Qiagen Sciences, Germantown, Maryland) for silica spin column capture and measured double-stranded DNA. Yields from frozen blood fractions were not statistically significantly different from those obtained from fresh fractions. ACP fractions yielded 80.6% (95% confidence interval: 66, 97) of the yield of frozen whole blood and 99.3% (95% confidence interval: 86, 100) of the yield of fresh blood. Frozen buffy coat and residual blood cells each yielded only half as much DNA as frozen ACP, and the yields were more variable. Assuming that DNA yield and quality from frozen ACP are stable, we recommend freezing plasma and ACP. Not only does ACP yield twice as much DNA as buffy coat but it is easier to process, and its yield is less variable from person to person. Long-term stability studies are needed. If one wishes to separate buffy coat before freezing, one should also save the residual blood cell fraction, which contains just as much DNA.
PMCID: PMC3783090  PMID: 23857774
all-cell-pellet fraction; buffy coat; DNA extraction yield; residual blood cells; whole blood
22.  Genetic Susceptibility to Chronic Lymphocytic Leukemia 
Seminars in hematology  2013;50(4):10.1053/j.seminhematol.2013.09.007.
Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the West and is an incurable malignancy. No firmly established evidence exists for environmental risk-factors in the etiology of CLL. However, CLL is estimated to have one of the highest familial risks for a hematologic malignancy; this along with other evidence strongly supports an inherited genetic component. In the past five years, genome-wide association studies have provided the foundation for new avenues in the investigation of pathogenesis of this disease with 22 susceptibility loci currently identified. We review here the advances made in identifying these loci, the potential to translate these findings into clinical practice, and future directions needed to advance our understanding of the genetic susceptibility of CLL.
PMCID: PMC3834539  PMID: 24246697
CLL; SNP associations; etiology
23.  Heme-related gene expression signatures of meat intakes in lung cancer tissues 
Molecular carcinogenesis  2013;53(7):548-556.
Lung cancer causes more deaths worldwide than any other cancer. In addition to cigarette smoking, dietary factors may contribute to lung carcinogenesis. Epidemiologic studies, including the Environment and Genetics in Lung cancer Etiology (EAGLE), have reported increased consumption of red/processed meats to be associated with higher risk of lung cancer. Heme-iron toxicity may link meat intake with cancer. We investigated this hypothesis in meat-related lung carcinogenesis using whole genome expression.
We measured genome-wide expression (HG-U133A) in 49 tumor and 42 non-involved fresh frozen lung tissues of 64 adenocarcinoma EAGLE patients. We studied gene expression profiles by high-versus-low meat consumption, with and without adjustment by sex, age, and smoking. Threshold for significance was a False Discovery Rate (FDR) ≤0.15. We studied whether the identified genes played a role in heme-iron related processes by means of manually curated literature search and gene ontology-based pathway analysis.
We found that gene expression of 232 annotated genes in tumor tissue significantly distinguished lung adenocarcinoma cases who consumed above/below the median intake of fresh red meats (FDR=0.12). Sixty-three (~28%) of the 232 identified genes (12 expected by chance, p-value<0.001) were involved in heme binding, absorption, transport, and Wnt signaling pathway (e.g., CYPs, TPO, HPX, HFE, SLCs, WNTs). We also identified several genes involved in lipid metabolism (e.g., NCR1, TNF, UCP3) and oxidative stress (e.g., TPO, SGK2, MTHFR) that may be indirectly related to heme-toxicity.
The study’s results provide preliminary evidence that heme-iron toxicity might be one underlying mechanism linking fresh red meat intake and lung cancer.
PMCID: PMC4152901  PMID: 23681825
24.  Characterizing the genetic basis of methylome diversity in histologically normal human lung tissue 
Nature communications  2014;5:3365.
The genetic regulation of the human epigenome is not fully appreciated. Here we describe the effects of genetic variants on the DNA methylome in human lung based on methylation-quantitative trait loci (meQTL) analyses. We report 34,304 cis- and 585 trans-meQTLs, a genetic-epigenetic interaction of surprising magnitude, including a regulatory hotspot. These findings are replicated in both breast and kidney tissues and show distinct patterns: cis-meQTLs mostly localize to CpG sites outside of genes, promoters, and CpG islands (CGIs), while trans-meQTLs are over-represented in promoter CGIs. meQTL SNPs are enriched in CTCF binding sites, DNaseI hypersensitivity regions and histone marks. Importantly, 4 of the 5 established lung cancer risk loci in European ancestry are cis-meQTLs and, in aggregate, cis-meQTLs are enriched for lung cancer risk in a genome-wide analysis of 11,587 subjects. Thus, inherited genetic variation may affect lung carcinogenesis by regulating the human methylome.
PMCID: PMC3982882  PMID: 24572595
25.  Reproductive and hormonal factors and the risk of lung cancer: the EAGLE Study 
Evidence about the role for reproductive and hormonal factors in the etiology of lung cancer in women is conflicting. To clarify this question, we examined 407 female cases and 499 female controls from the Environment And Genetics in Lung cancer Etiology (EAGLE) population-based case-control study. Subjects were interviewed in person using a computer-assisted personal interview to assess demographics, education, smoking history, medical history, occupational history, reproductive and hormonal factors. Associations of interest were investigated using logistic regression models, adjusted for catchment area and age (matching variables), cigarette smoking (status, pack-years, and time since quitting). Additional confounding variables were investigated but did not substantially affect the results. We observed a reduced risk of lung cancer among women with later age at first live birth (≥31 years: OR=0.57, 95%CI=0.31–1.06, p-trend=0.05), later age at menopause (≥51 years: OR=0.49, 95%CI=0.31–0.79, p-trend=0.003), and longer reproductive periods (≥41 years: OR=0.44, 95%CI=0.25–0.79, p-trend=0.01). A reduced risk was also observed for Hormone Replacement Therapy (OR=0.63, 95%CI=0.42–0.95, p=0.03) and oral contraceptive use (OR=0.67, 95%CI=0.45–1.00, p=0.05), but no trend with duration of use was detected. Menopausal status (both natural and induced) was associated with an augmented risk. No additional associations were identified for other reproductive variables. This study suggests that women who continue to produce estrogens have a lower lung cancer risk. Large studies with great number of never smoking women, biomarkers of estrogen and molecular classification of lung cancer are needed for a more comprehensive view of the association between reproductive factors and lung cancer risk.
PMCID: PMC3609937  PMID: 23129166
case-control study; lung cancer; reproductive factors

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