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author:("capgras, Neil")
1.  Use of Multiple Imputation to Correct for Bias in Lung Cancer Incidence Trends by Histologic Subtype 
Background
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.
Methods
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.
Results
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.
Conclusions
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.
Impact
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.
doi:10.1158/1055-9965.EPI-14-0130
PMCID: PMC4119525  PMID: 24855099
SEER; ICD-O-3; Non-specific morphology codes; Missing data; Ridge-penalized logistic regression
2.  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.
doi:10.1158/0008-5472.CAN-14-0459
PMCID: PMC4119534  PMID: 24853549
Leukocytes; Lung cancer; Prospective; Telomeres
3.  Genome-wide interaction study of smoking and bladder cancer risk 
Carcinogenesis  2014;35(8):1737-1744.
Summary
Our GWAS of smoking and bladder cancer risk based on data from 5,424 cases and 10,162 controls suggest that exploring additive and multiplicative gene–environment interactions can identify novel susceptibility loci that are associated with risk for different subgroups.
Bladder cancer is a complex disease with known environmental and genetic risk factors. We performed a genome-wide interaction study (GWAS) of smoking and bladder cancer risk based on primary scan data from 3002 cases and 4411 controls from the National Cancer Institute Bladder Cancer GWAS. Alternative methods were used to evaluate both additive and multiplicative interactions between individual single nucleotide polymorphisms (SNPs) and smoking exposure. SNPs with interaction P values < 5 × 10− 5 were evaluated further in an independent dataset of 2422 bladder cancer cases and 5751 controls. We identified 10 SNPs that showed association in a consistent manner with the initial dataset and in the combined dataset, providing evidence of interaction with tobacco use. Further, two of these novel SNPs showed strong evidence of association with bladder cancer in tobacco use subgroups that approached genome-wide significance. Specifically, rs1711973 (FOXF2) on 6p25.3 was a susceptibility SNP for never smokers [combined odds ratio (OR) = 1.34, 95% confidence interval (CI) = 1.20–1.50, P value = 5.18 × 10− 7]; and rs12216499 (RSPH3-TAGAP-EZR) on 6q25.3 was a susceptibility SNP for ever smokers (combined OR = 0.75, 95% CI = 0.67–0.84, P value = 6.35 × 10− 7). In our analysis of smoking and bladder cancer, the tests for multiplicative interaction seemed to more commonly identify susceptibility loci with associations in never smokers, whereas the additive interaction analysis identified more loci with associations among smokers—including the known smoking and NAT2 acetylation interaction. Our findings provide additional evidence of gene–environment interactions for tobacco and bladder cancer.
doi:10.1093/carcin/bgu064
PMCID: PMC4123644  PMID: 24662972
4.  Metabolites of tobacco smoking and colorectal cancer risk 
Carcinogenesis  2014;35(7):1516-1522.
Summary
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.
doi:10.1093/carcin/bgu071
PMCID: PMC4076812  PMID: 24648381
5.  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.
doi:10.1002/ijc.28986
PMCID: PMC4477910  PMID: 24861979
lung neoplasms; case–control studies; bricklayers; occupational health; epidemiology
6.  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.
doi:10.1093/carcin/bgu038
PMCID: PMC4043241  PMID: 24523449
7.  Time to Smoke First Morning Cigarette and Lung Cancer in a Case–Control Study 
Background
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).
Methods
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.
Results
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).
Conclusions
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.
doi:10.1093/jnci/dju118
PMCID: PMC4072901  PMID: 24948709
8.  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.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1371/journal.pone.0125973
PMCID: PMC4436174  PMID: 25985429
9.  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.
doi:10.1158/0008-5472.CAN-14-1531
PMCID: PMC4203382  PMID: 25320178
Aggressive bladder cancer; cyclin E; cell cycle; single nucleotide polymorphism; GWAS
10.  Genome-wide association study identifies multiple loci associated with bladder cancer risk 
Figueroa, Jonine D. | Ye, Yuanqing | Siddiq, Afshan | Garcia-Closas, Montserrat | Chatterjee, Nilanjan | Prokunina-Olsson, Ludmila | Cortessis, Victoria K. | Kooperberg, Charles | Cussenot, Olivier | Benhamou, Simone | Prescott, Jennifer | Porru, Stefano | Dinney, Colin P. | Malats, Núria | Baris, Dalsu | Purdue, Mark | Jacobs, Eric J. | Albanes, Demetrius | Wang, Zhaoming | Deng, Xiang | Chung, Charles C. | Tang, Wei | Bas Bueno-de-Mesquita, H. | Trichopoulos, Dimitrios | Ljungberg, Börje | Clavel-Chapelon, Françoise | Weiderpass, Elisabete | Krogh, Vittorio | Dorronsoro, Miren | Travis, Ruth | Tjønneland, Anne | Brenan, Paul | Chang-Claude, Jenny | Riboli, Elio | Conti, David | Gago-Dominguez, Manuela | Stern, Mariana C. | Pike, Malcolm C. | Van Den Berg, David | Yuan, Jian-Min | Hohensee, Chancellor | Rodabough, Rebecca | Cancel-Tassin, Geraldine | Roupret, Morgan | Comperat, Eva | Chen, Constance | De Vivo, Immaculata | Giovannucci, Edward | Hunter, David J. | Kraft, Peter | Lindstrom, Sara | Carta, Angela | Pavanello, Sofia | Arici, Cecilia | Mastrangelo, Giuseppe | Kamat, Ashish M. | Lerner, Seth P. | Barton Grossman, H. | Lin, Jie | Gu, Jian | Pu, Xia | Hutchinson, Amy | Burdette, Laurie | Wheeler, William | Kogevinas, Manolis | Tardón, Adonina | Serra, Consol | Carrato, Alfredo | García-Closas, Reina | Lloreta, Josep | Schwenn, Molly | Karagas, Margaret R. | Johnson, Alison | Schned, Alan | Armenti, Karla R. | Hosain, G.M. | Andriole, Gerald | Grubb, Robert | Black, Amanda | Ryan Diver, W. | Gapstur, Susan M. | Weinstein, Stephanie J. | Virtamo, Jarmo | Haiman, Chris A. | Landi, Maria T. | Caporaso, Neil | Fraumeni, Joseph F. | Vineis, Paolo | Wu, Xifeng | Silverman, Debra T. | Chanock, Stephen | Rothman, Nathaniel
Human Molecular Genetics  2013;23(5):1387-1398.
Candidate gene and genome-wide association studies (GWAS) have identified 11 independent susceptibility loci associated with bladder cancer risk. To discover additional risk variants, we conducted a new GWAS of 2422 bladder cancer cases and 5751 controls, followed by a meta-analysis with two independently published bladder cancer GWAS, resulting in a combined analysis of 6911 cases and 11 814 controls of European descent. TaqMan genotyping of 13 promising single nucleotide polymorphisms with P < 1 × 10−5 was pursued in a follow-up set of 801 cases and 1307 controls. Two new loci achieved genome-wide statistical significance: rs10936599 on 3q26.2 (P = 4.53 × 10−9) and rs907611 on 11p15.5 (P = 4.11 × 10−8). Two notable loci were also identified that approached genome-wide statistical significance: rs6104690 on 20p12.2 (P = 7.13 × 10−7) and rs4510656 on 6p22.3 (P = 6.98 × 10−7); these require further studies for confirmation. In conclusion, our study has identified new susceptibility alleles for bladder cancer risk that require fine-mapping and laboratory investigation, which could further understanding into the biological underpinnings of bladder carcinogenesis.
doi:10.1093/hmg/ddt519
PMCID: PMC3919005  PMID: 24163127
11.  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.
doi:10.1038/ng.3052
PMCID: PMC4191666  PMID: 25086665
12.  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
13.  Circulating Inflammation Markers and Prospective Risk for Lung Cancer 
Background
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.
Methods
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.
Results
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.
Conclusions
Some circulating inflammation marker levels are associated with prospective lung cancer risk.
doi:10.1093/jnci/djt309
PMCID: PMC3888091  PMID: 24249745
16.  Welding and Lung Cancer in a Pooled Analysis of Case-Control Studies 
American Journal of Epidemiology  2013;178(10):1513-1525.
Several epidemiologic studies have indicated an increased risk of lung cancer among welders. We used the SYNERGY project database to assess welding as a risk factor for developing lung cancer. The database includes data on 15,483 male lung cancer cases and 18,388 male controls from 16 studies in Europe, Canada, China, and New Zealand conducted between 1985 and 2010. Odds ratios and 95% confidence intervals between regular or occasional welding and lung cancer were estimated, with adjustment for smoking, age, study center, and employment in other occupations associated with lung cancer risk. Overall, 568 cases and 427 controls had ever worked as welders and had an odds ratio of developing lung cancer of 1.44 (95% confidence interval: 1.25, 1.67) with the odds ratio increasing for longer duration of welding. In never and light smokers, the odds ratio was 1.96 (95% confidence interval: 1.37, 2.79). The odds ratios were somewhat higher for squamous and small cell lung cancers than for adenocarcinoma. Another 1,994 cases and 1,930 controls had ever worked in occupations with occasional welding. Work in any of these occupations was associated with some elevation of risk, though not as much as observed in regular welders. Our findings lend further support to the hypothesis that welding is associated with an increased risk of lung cancer.
doi:10.1093/aje/kwt201
PMCID: PMC3888276  PMID: 24052544
case-control studies; lung cancer; occupational exposure; welding
17.  Lung Cancer Risk Among Hairdressers: A Pooled Analysis of Case-Control Studies Conducted Between 1985 and 2010 
American Journal of Epidemiology  2013;178(9):1355-1365.
Increased lung cancer risks among hairdressers were observed in large registry-based cohort studies from Scandinavia, but these studies could not adjust for smoking. Our objective was to evaluate the lung cancer risk among hairdressers while adjusting for smoking and other confounders in a pooled database of 16 case-control studies conducted in Europe, Canada, China, and New Zealand between 1985 and 2010 (the Pooled Analysis of Case-Control Studies on the Joint Effects of Occupational Carcinogens in the Development of Lung Cancer). Lifetime occupational and smoking information was collected through interviews with 19,369 cases of lung cancer and 23,674 matched population or hospital controls. Overall, 170 cases and 167 controls had ever worked as hairdresser or barber. The odds ratios for lung cancer in women were 1.65 (95% confidence interval (CI): 1.16, 2.35) without adjustment for smoking and 1.12 (95% CI: 0.75, 1.68) with adjustment for smoking; however, women employed before 1954 also experienced an increased lung cancer risk after adjustment for smoking (odds ratio = 2.66, 95% CI: 1.09, 6.47). The odds ratios in male hairdressers/barbers were generally not elevated, except for an increased odds ratio for adenocarcinoma in long-term barbers (odds ratio = 2.20, 95% CI: 1.02, 4.77). Our results suggest that the increased lung cancer risks among hairdressers are due to their smoking behavior; single elevated risk estimates should be interpreted with caution and need replication in other studies.
doi:10.1093/aje/kwt119
PMCID: PMC3813309  PMID: 24068200
case-control studies; hair bleaching agents; hair color; lung neoplasms; occupational exposure
18.  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.
doi:10.1038/ng.2941
PMCID: PMC4056593  PMID: 24686846
19.  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.
doi:10.1093/aje/kwt079
PMCID: PMC3783090  PMID: 23857774
all-cell-pellet fraction; buffy coat; DNA extraction yield; residual blood cells; whole blood
20.  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.
doi:10.1053/j.seminhematol.2013.09.007
PMCID: PMC3834539  PMID: 24246697
CLL; SNP associations; etiology
21.  Genome-wide association analysis identifies new lung cancer susceptibility loci in never-smoking women in Asia 
Lan, Qing | Hsiung, Chao A | Matsuo, Keitaro | Hong, Yun-Chul | Seow, Adeline | Wang, Zhaoming | Hosgood, H Dean | Chen, Kexin | Wang, Jiu-Cun | Chatterjee, Nilanjan | Hu, Wei | Wong, Maria Pik | Zheng, Wei | Caporaso, Neil | Park, Jae Yong | Chen, Chien-Jen | Kim, Yeul Hong | Kim, Young Tae | Landi, Maria Teresa | Shen, Hongbing | Lawrence, Charles | Burdett, Laurie | Yeager, Meredith | Yuenger, Jeffrey | Jacobs, Kevin B | Chang, I-Shou | Mitsudomi, Tetsuya | Kim, Hee Nam | Chang, Gee-Chen | Bassig, Bryan A | Tucker, Margaret | Wei, Fusheng | Yin, Zhihua | Wu, Chen | An, She-Juan | Qian, Biyun | Lee, Victor Ho Fun | Lu, Daru | Liu, Jianjun | Jeon, Hyo-Sung | Hsiao, Chin-Fu | Sung, Jae Sook | Kim, Jin Hee | Gao, Yu-Tang | Tsai, Ying-Huang | Jung, Yoo Jin | Guo, Huan | Hu, Zhibin | Hutchinson, Amy | Wang, Wen-Chang | Klein, Robert | Chung, Charles C | Oh, In-Jae | Chen, Kuan-Yu | Berndt, Sonja I | He, Xingzhou | Wu, Wei | Chang, Jiang | Zhang, Xu-Chao | Huang, Ming-Shyan | Zheng, Hong | Wang, Junwen | Zhao, Xueying | Li, Yuqing | Choi, Jin Eun | Su, Wu-Chou | Park, Kyong Hwa | Sung, Sook Whan | Shu, Xiao-Ou | Chen, Yuh-Min | Liu, Li | Kang, Chang Hyun | Hu, Lingmin | Chen, Chung-Hsing | Pao, William | Kim, Young-Chul | Yang, Tsung-Ying | Xu, Jun | Guan, Peng | Tan, Wen | Su, Jian | Wang, Chih-Liang | Li, Haixin | Sihoe, Alan Dart Loon | Zhao, Zhenhong | Chen, Ying | Choi, Yi Young | Hung, Jen-Yu | Kim, Jun Suk | Yoon, Ho-Il | Cai, Qiuyin | Lin, Chien-Chung | Park, In Kyu | Xu, Ping | Dong, Jing | Kim, Christopher | He, Qincheng | Perng, Reury-Perng | Kohno, Takashi | Kweon, Sun-Seog | Chen, Chih-Yi | Vermeulen, Roel | Wu, Junjie | Lim, Wei-Yen | Chen, Kun-Chieh | Chow, Wong-Ho | Ji, Bu-Tian | Chan, John K C | Chu, Minjie | Li1, Yao-Jen | Yokota, Jun | Li, Jihua | Chen, Hongyan | Xiang, Yong-Bing | Yu, Chong-Jen | Kunitoh, Hideo | Wu, Guoping | Jin, Li | Lo, Yen-Li | Shiraishi, Kouya | Chen, Ying-Hsiang | Lin, Hsien-Chih | Wu, Tangchun | Wu, Yi-Long | Yang, Pan-Chyr | Zhou, Baosen | Shin, Min-Ho | Fraumeni, Joseph F | Lin, Dongxin | Chanock, Stephen J | Rothman, Nathaniel
Nature genetics  2012;44(12):1330-1335.
To identify common genetic variants that contribute to lung cancer susceptibility, we conducted a multistage genome-wide association study of lung cancer in Asian women who never smoked. We scanned 5,510 never-smoking female lung cancer cases and 4,544 controls drawn from 14 studies from mainland China, South Korea, Japan, Singapore, Taiwan, and Hong Kong. We genotyped the most promising variants (associated at P < 5 × 10-6) in an additional 1,099 cases and 2,913 controls. We identified three new susceptibility loci at 10q25.2 (rs7086803, P = 3.54 × 10-18), 6q22.2 (rs9387478, P = 4.14 × 10-10) and 6p21.32 (rs2395185, P = 9.51 × 10-9). We also confirmed associations reported for loci at 5p15.33 and 3q28 and a recently reported finding at 17q24.3. We observed no evidence of association for lung cancer at 15q25 in never-smoking women in Asia, providing strong evidence that this locus is not associated with lung cancer independent of smoking.
doi:10.1038/ng.2456
PMCID: PMC4169232  PMID: 23143601
22.  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.
doi:10.1002/mc.22006
PMCID: PMC4152901  PMID: 23681825
23.  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.
doi:10.1038/ncomms4365
PMCID: PMC3982882  PMID: 24572595
24.  Racial Disparities in the Prevalence of Monoclonal Gammopathies: A population-based study of 12,482 persons from the National Health and Nutritional Examination Survey 
Leukemia  2014;28(7):1537-1542.
Background
The incidence of multiple myeloma (MM) is markedly higher in blacks compared with whites. This may be related to a higher prevalence of monoclonal gammopathy of undetermined significance (MGUS), the premalignant lesion that precedes MM. Our objective was to define the prevalence and risk factors of MGUS in blacks, Hispanics, and whites using a large cohort representative of the United States (U.S.) population.
Methods
Of 13,278 adults age ≥50 years enrolled in National Health and Nutritional Examination Survey (NHANES) III or NHANES 1999–2004, stored serum samples to test for monoclonal proteins were available on 12,482 persons (2,331 non-Hispanic blacks considered “black”, 2,475 Hispanics, 7,051 non-Hispanic whites considered “white”, and 625 “others”). Agarose-gel electrophoresis, serum protein immunofixation, serum free light-chain assay, and typing of the M-protein was performed on sera from all subjects. Unadjusted and adjusted prevalence rates were computed from logistic regression analysis. Risk factors were studied using available survey information available from NHANES. Main outcomes and measures were prevalence of MGUS by age, gender, race, ethnicity, and risk factors from available survey information.
Findings
MGUS was identified in 365 participants, for an overall prevalence of 2.4%. Adjusted prevalence of MGUS was significantly higher (p<0.001) in blacks (3.7%) compared with whites (2.3%) (p=0.001) or Hispanics (1.8%). MGUS in blacks had characteristics that posed a greater risk of progression to MM. The prevalence of MGUS (adjusted for age, education, sex, race, smoking) was 3.1% and 2.1% for the North and Midwest versus South and West regions of the U.S., respectively (p=0.052).
Interpretation
MGUS is significantly more common in blacks, and more often has features associated with higher risk of progression to MM. We also find a strong geographic disparity in the prevalence of MGUS between the North/Midwest versus the South/West regions of the U.S., which has etiologic implications.
doi:10.1038/leu.2014.34
PMCID: PMC4090286  PMID: 24441287
monoclonal gammopathy; prevalence; prognosis; biomarker; racial disparity
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.
doi:10.1002/ijc.27926
PMCID: PMC3609937  PMID: 23129166
case-control study; lung cancer; reproductive factors

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