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author:("capgras, Neil")
1.  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
2.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
11.  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
12.  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
13.  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
14.  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
15.  Precursors to Lymphoproliferative Malignancies 
We review monoclonal B-cell lymphocytosis (MBL) as a precursor to chronic lymphocytic leukemia and monoclonal gammopathy of undetermined significance (MGUS) as a precursor to plasma cell disorders. These conditions are present in the general population and increase with age. These precursors aggregate with lymphoproliferative malignancies in families suggesting shared inheritance. MBL and MGUS may share some of the same risk factors as their related malignancies but data are limited. While these conditions are characterized by enhanced risk for the associated malignancy, the majority of individuals with these conditions do not progress to malignancy. A key focus for current work is to identify markers that predict progression to malignancy.
doi:10.1158/1055-9965.EPI-12-1348
PMCID: PMC3616401  PMID: 23549397
16.  Are Women Who Smoke at Higher Risk for Lung Cancer Than Men Who Smoke? 
American Journal of Epidemiology  2013;177(7):601-612.
Worldwide lung cancer incidence is decreasing or leveling off among men, but rising among women. Sex differences in associations of tobacco carcinogens with lung cancer risk have been hypothesized, but the epidemiologic evidence is conflicting. We tested sex-smoking interaction in association with lung cancer risk within a population-based case-control study, the Environment and Genetics in Lung Cancer Etiology (EAGLE) Study (Lombardy, Italy, 2002–2005). Detailed lifetime smoking histories were collected by personal interview in 2,100 cases with incident lung cancer and 2,120 controls. Odds ratios and 95% confidence intervals for pack-years of cigarette smoking were estimated by logistic regression, adjusted for age, residence area, and time since quitting smoking. To assess sex-smoking interaction, we compared the slopes of odds ratios for logarithm of pack-years in a model for men and women combined. Overall, the slope for pack-years was steeper in men (odds ratio for female-smoking interaction = 0.39, 95% confidence interval: 0.24, 0.62; P < 0.0001); after restriction to ever smokers, the difference in slopes was much smaller (odds ratio for interaction = 0.63, 95% confidence interval: 0.29, 1.37; P = 0.24). Similar results were found by histological type. Results were unchanged when additional confounders were evaluated (e.g., tobacco type, inhalation depth, Fagerström-assessed nicotine dependence). These findings do not support a higher female susceptibility to tobacco-related lung cancer.
doi:10.1093/aje/kws445
PMCID: PMC3657535  PMID: 23425629
case-control studies; lung cancer; sex differences; smoking
17.  Common genetic polymorphisms modify the effect of smoking on absolute risk of bladder cancer 
Cancer research  2013;73(7):2211-2220.
Bladder cancer results from the combined effects of environmental and genetic factors, smoking being the strongest risk factor. Evaluating absolute risks resulting from the joint effects of smoking and genetic factors is critical to evaluate the public health relevance of genetic information. Analyses included up to 3,942 cases and 5,680 controls of European background in seven studies. We tested for multiplicative and additive interactions between smoking and 12 susceptibility loci, individually and combined as a polygenic risk score (PRS). Thirty-year absolute risks and risk differences by levels of the PRS were estimated for US-males aged 50-years. Six out of 12 variants showed significant additive gene-environment interactions, most notably NAT2 (P=7×10-4) and UGT1A6 (P=8×10-4). The 30-year absolute risk of bladder cancer in US males was 6.2% for all current smokers. This risk ranged from 2.9% for current smokers in the lowest quartile of the PRS to 9.9% for current smokers in the upper quartile. Risk difference estimates indicated that 8,200 cases would be prevented if elimination of smoking occurred in 100,000 men in the upper PRS quartile, compared to 2,000 cases prevented by a similar effort in the lowest PRS quartile (P-additive =1×10-4). The impact of eliminating smoking the on number of bladder cancer cases prevented is larger for individuals at higher than lower genetic risk. Our findings could have implications for targeted prevention strategies. However, other smoking-related diseases, as well as practical and ethical considerations, need to be considered before any recommendations could be made.
doi:10.1158/0008-5472.CAN-12-2388
PMCID: PMC3688270  PMID: 23536561
18.  Pleiotropic Associations of Risk Variants Identified for Other Cancers With Lung Cancer Risk: The PAGE and TRICL Consortia 
Background
Genome-wide association studies have identified hundreds of genetic variants associated with specific cancers. A few of these risk regions have been associated with more than one cancer site; however, a systematic evaluation of the associations between risk variants for other cancers and lung cancer risk has yet to be performed.
Methods
We included 18023 patients with lung cancer and 60543 control subjects from two consortia, Population Architecture using Genomics and Epidemiology (PAGE) and Transdisciplinary Research in Cancer of the Lung (TRICL). We examined 165 single-nucleotide polymorphisms (SNPs) that were previously associated with at least one of 16 non–lung cancer sites. Study-specific logistic regression results underwent meta-analysis, and associations were also examined by race/ethnicity, histological cell type, sex, and smoking status. A Bonferroni-corrected P value of 2.5×10–5 was used to assign statistical significance.
Results
The breast cancer SNP LSP1 rs3817198 was associated with an increased risk of lung cancer (odds ratio [OR] = 1.10; 95% confidence interval [CI] = 1.05 to 1.14; P = 2.8×10–6). This association was strongest for women with adenocarcinoma (P = 1.2×10–4) and not statistically significant in men (P = .14) with this cell type (P het by sex = .10). Two glioma risk variants, TERT rs2853676 and CDKN2BAS1 rs4977756, which are located in regions previously associated with lung cancer, were associated with increased risk of adenocarcinoma (OR = 1.16; 95% CI = 1.10 to 1.22; P = 1.1×10–8) and squamous cell carcinoma (OR = 1.13; CI = 1.07 to 1.19; P = 2.5×10–5), respectively.
Conclusions
Our findings demonstrate a novel pleiotropic association between the breast cancer LSP1 risk region marked by variant rs3817198 and lung cancer risk.
doi:10.1093/jnci/dju061
PMCID: PMC3982896  PMID: 24681604
19.  VTET: a variable threshold exact test for identifying disease-associated copy number variations enriched in short genomic regions 
Copy number variations (CNVs) constitute a major source of genetic variations in human populations and have been reported to be associated with complex diseases. Methods have been developed for detecting CNVs and testing CNV associations in genome-wide association studies (GWAS) based on SNP arrays. Commonly used two-step testing procedures work well only for long CNVs while direct CNV association testing methods work only for recurrent CNVs. Assuming that short CNVs disrupting any part of a given genomic region increase disease risk, we developed a variable threshold exact test (VTET) for testing disease associations of CNVs randomly distributed in the genome using intensity data from SNP arrays. By extensive simulations, we found that VTET outperformed two-step testing procedures based on existing CNV calling algorithms for short CNVs and that the performance of VTET was robust to the length of the genomic region. In addition, VTET had a comparable performance with CNVtools for testing the association of recurrent CNVs. Thus, we expect VTET to be useful for testing disease associations of both recurrent and randomly distributed CNVs using existing GWAS data. We applied VTET to a lung cancer GWAS and identified a genome-wide significant region on chromosome 18q22.3 for lung squamous cell carcinoma.
doi:10.3389/fgene.2014.00053
PMCID: PMC3957064  PMID: 24672538
copy number varination; variable threshold exact test; genome-wide association study; interval-based association test; lung cancer CNV analysis
20.  Distinct Loci in the CHRNA5/CHRNA3/CHRNB4 Gene Cluster Are Associated With Onset of Regular Smoking 
Stephens, Sarah H. | Hartz, Sarah M. | Hoft, Nicole R. | Saccone, Nancy L. | Corley, Robin C. | Hewitt, John K. | Hopfer, Christian J. | Breslau, Naomi | Coon, Hilary | Chen, Xiangning | Ducci, Francesca | Dueker, Nicole | Franceschini, Nora | Frank, Josef | Han, Younghun | Hansel, Nadia N. | Jiang, Chenhui | Korhonen, Tellervo | Lind, Penelope A. | Liu, Jason | Lyytikäinen, Leo-Pekka | Michel, Martha | Shaffer, John R. | Short, Susan E. | Sun, Juzhong | Teumer, Alexander | Thompson, John R. | Vogelzangs, Nicole | Vink, Jacqueline M. | Wenzlaff, Angela | Wheeler, William | Yang, Bao-Zhu | Aggen, Steven H. | Balmforth, Anthony J. | Baumeister, Sebastian E. | Beaty, Terri H. | Benjamin, Daniel J. | Bergen, Andrew W. | Broms, Ulla | Cesarini, David | Chatterjee, Nilanjan | Chen, Jingchun | Cheng, Yu-Ching | Cichon, Sven | Couper, David | Cucca, Francesco | Dick, Danielle | Foroud, Tatiana | Furberg, Helena | Giegling, Ina | Gillespie, Nathan A. | Gu, Fangyi | Hall, Alistair S. | Hällfors, Jenni | Han, Shizhong | Hartmann, Annette M. | Heikkilä, Kauko | Hickie, Ian B. | Hottenga, Jouke Jan | Jousilahti, Pekka | Kaakinen, Marika | Kähönen, Mika | Koellinger, Philipp D. | Kittner, Stephen | Konte, Bettina | Landi, Maria-Teresa | Laatikainen, Tiina | Leppert, Mark | Levy, Steven M. | Mathias, Rasika A. | McNeil, Daniel W. | Medland, Sarah E. | Montgomery, Grant W. | Murray, Tanda | Nauck, Matthias | North, Kari E. | Paré, Peter D. | Pergadia, Michele | Ruczinski, Ingo | Salomaa, Veikko | Viikari, Jorma | Willemsen, Gonneke | Barnes, Kathleen C. | Boerwinkle, Eric | Boomsma, Dorret I. | Caporaso, Neil | Edenberg, Howard J. | Francks, Clyde | Gelernter, Joel | Grabe, Hans Jörgen | Hops, Hyman | Jarvelin, Marjo-Riitta | Johannesson, Magnus | Kendler, Kenneth S. | Lehtimäki, Terho | Magnusson, Patrik K.E. | Marazita, Mary L. | Marchini, Jonathan | Mitchell, Braxton D. | Nöthen, Markus M. | Penninx, Brenda W. | Raitakari, Olli | Rietschel, Marcella | Rujescu, Dan | Samani, Nilesh J. | Schwartz, Ann G. | Shete, Sanjay | Spitz, Margaret | Swan, Gary E. | Völzke, Henry | Veijola, Juha | Wei, Qingyi | Amos, Chris | Cannon, Dale S. | Grucza, Richard | Hatsukami, Dorothy | Heath, Andrew | Johnson, Eric O. | Kaprio, Jaakko | Madden, Pamela | Martin, Nicholas G. | Stevens, Victoria L. | Weiss, Robert B. | Kraft, Peter | Bierut, Laura J. | Ehringer, Marissa A.
Genetic epidemiology  2013;37(8):846-859.
Neuronal nicotinic acetylcholine receptor (nAChR) genes (CHRNA5/CHRNA3/CHRNB4) have been reproducibly associated with nicotine dependence, smoking behaviors, and lung cancer risk. Of the few reports that have focused on early smoking behaviors, association results have been mixed. This meta-analysis examines early smoking phenotypes and SNPs in the gene cluster to determine: (1) whether the most robust association signal in this region (rs16969968) for other smoking behaviors is also associated with early behaviors, and/or (2) if additional statistically independent signals are important in early smoking. We focused on two phenotypes: age of tobacco initiation (AOI) and age of first regular tobacco use (AOS). This study included 56,034 subjects (41 groups) spanning nine countries and evaluated five SNPs including rs1948, rs16969968, rs578776, rs588765, and rs684513. Each dataset was analyzed using a centrally generated script. Meta-analyses were conducted from summary statistics. AOS yielded significant associations with SNPs rs578776 (beta = 0.02, P = 0.004), rs1948 (beta = 0.023, P = 0.018), and rs684513 (beta = 0.032, P = 0.017), indicating protective effects. There were no significant associations for the AOI phenotype. Importantly, rs16969968, the most replicated signal in this region for nicotine dependence, cigarettes per day, and cotinine levels, was not associated with AOI (P = 0.59) or AOS (P = 0.92). These results provide important insight into the complexity of smoking behavior phenotypes, and suggest that association signals in the CHRNA5/A3/B4 gene cluster affecting early smoking behaviors may be different from those affecting the mature nicotine dependence phenotype.
doi:10.1002/gepi.21760
PMCID: PMC3947535  PMID: 24186853
CHRNA5; CHRNA3; CHRNB4; meta-analysis; nicotine; smoke
21.  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 
Background
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.
Methods
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.
Results
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).
Conclusions
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.
Impact
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.
doi:10.1158/1055-9965.EPI-12-1217
PMCID: PMC3596428  PMID: 23307532
CLL; NHL; SNPs; IRF8; risk locus
22.  Selection Criteria for Lung-Cancer Screening 
The New England journal of medicine  2013;368(8):728-736.
BACKGROUND
The National Lung Screening Trial (NLST) used risk factors for lung cancer (e.g., ≥30 pack-years of smoking and <15 years since quitting) as selection criteria for lung-cancer screening. Use of an accurate model that incorporates additional risk factors to select persons for screening may identify more persons who have lung cancer or in whom lung cancer will develop.
METHODS
We modified the 2011 lung-cancer risk-prediction model from our Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial to ensure applicability to NLST data; risk was the probability of a diagnosis of lung cancer during the 6-year study period. We developed and validated the model (PLCOM2012) with data from the 80,375 persons in the PLCO control and intervention groups who had ever smoked. Discrimination (area under the receiver-operating-characteristic curve [AUC]) and calibration were assessed. In the validation data set, 14,144 of 37,332 persons (37.9%) met NLST criteria. For comparison, 14,144 highest-risk persons were considered positive (eligible for screening) according to PLCOM2012 criteria. We compared the accuracy of PLCOM2012 criteria with NLST criteria to detect lung cancer. Cox models were used to evaluate whether the reduction in mortality among 53,202 persons undergoing low-dose computed tomographic screening in the NLST differed according to risk.
RESULTS
The AUC was 0.803 in the development data set and 0.797 in the validation data set. As compared with NLST criteria, PLCOM2012 criteria had improved sensitivity (83.0% vs. 71.1%, P<0.001) and positive predictive value (4.0% vs. 3.4%, P = 0.01), without loss of specificity (62.9% and. 62.7%, respectively; P = 0.54); 41.3% fewer lung cancers were missed. The NLST screening effect did not vary according to PLCOM2012 risk (P = 0.61 for interaction).
CONCLUSIONS
The use of the PLCOM2012 model was more sensitive than the NLST criteria for lung-cancer detection.
doi:10.1056/NEJMoa1211776
PMCID: PMC3929969  PMID: 23425165
23.  Genome-wide Association Study Identifies Two Susceptibility Loci for Osteosarcoma 
Nature genetics  2013;45(7):799-803.
Osteosarcoma is the most common primary bone malignancy of adolescents and young adults. In order to better understand the genetic etiology of osteosarcoma, we performed a multi-stage genome-wide association study (GWAS) consisting of 941 cases and 3,291 cancer-free adult controls of European ancestry. Two loci achieved genome-wide significance: rs1906953 at 6p21.3, in the glutamate receptor metabotropic 4 [GRM4] gene (P = 8.1 ×10-9), and rs7591996 and rs10208273 in a gene desert on 2p25.2 (P = 1.0 ×10-8 and 2.9 ×10-7). These two susceptibility loci warrant further exploration to uncover the biological mechanisms underlying susceptibility to osteosarcoma.
doi:10.1038/ng.2645
PMCID: PMC3910497  PMID: 23727862
25.  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.
doi:10.1038/ng.2652
PMCID: PMC3729927  PMID: 23770605

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