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1.  Pooling prospective studies to investigate the etiology of second cancers 
Background
With over 13 million cancer survivors in the United States today, second cancers are of rapidly growing importance. However, data on non-treatment risk factors for second cancers are sparse. We explored the feasibility of pooling data from cohort studies of cancer incidence to investigate second cancer etiology.
Methods
We combined data from five prospective studies including more than 800,000 individuals. We compared study designs and populations; evaluated availability of and ability to harmonize risk factor data; compared incidence and survival for common first primary malignancies and incidence of second primary malignancies; and estimated sample size requirements.
Results
Overall, 96,513 incident, first primary malignancies were diagnosed during 1985–2009. Incidence rates and survival following the first primary varied among the cohorts, but most of the heterogeneity could be explained by characteristics of the study populations (age, sex, smoking, and screening rates). 7,890 second primary cancers (excluding original primary site) were identified, yielding sufficient statistical power (≥80%) for detecting modest associations with risk of all second cancers among survivors of common first primary malignancies (e.g., colorectal cancer); however, there were insufficient events for studying survivors of rarer cancers or identifying risk factors for specific second cancers.
Conclusions
Pooling data from cohort studies to investigate non-treatment risk factors for second primary cancers appears feasible but there are important methodological issues - some of which are barriers to specific research questions - that require special attention.
Impact
Increased understanding of non-treatment risk factors for second cancers will provide valuable prevention and surveillance information.
doi:10.1158/1055-9965.EPI-14-0191
PMCID: PMC4119533  PMID: 24832874
2.  Etiologic Heterogeneity Among Non-Hodgkin Lymphoma Subtypes: The InterLymph Non-Hodgkin Lymphoma Subtypes Project 
Morton, Lindsay M. | Slager, Susan L. | Cerhan, James R. | Wang, Sophia S. | Vajdic, Claire M. | Skibola, Christine F. | Bracci, Paige M. | de Sanjosé, Silvia | Smedby, Karin E. | Chiu, Brian C. H. | Zhang, Yawei | Mbulaiteye, Sam M. | Monnereau, Alain | Turner, Jennifer J. | Clavel, Jacqueline | Adami, Hans-Olov | Chang, Ellen T. | Glimelius, Bengt | Hjalgrim, Henrik | Melbye, Mads | Crosignani, Paolo | di Lollo, Simonetta | Miligi, Lucia | Nanni, Oriana | Ramazzotti, Valerio | Rodella, Stefania | Costantini, Adele Seniori | Stagnaro, Emanuele | Tumino, Rosario | Vindigni, Carla | Vineis, Paolo | Becker, Nikolaus | Benavente, Yolanda | Boffetta, Paolo | Brennan, Paul | Cocco, Pierluigi | Foretova, Lenka | Maynadié, Marc | Nieters, Alexandra | Staines, Anthony | Colt, Joanne S. | Cozen, Wendy | Davis, Scott | de Roos, Anneclaire J. | Hartge, Patricia | Rothman, Nathaniel | Severson, Richard K. | Holly, Elizabeth A. | Call, Timothy G. | Feldman, Andrew L. | Habermann, Thomas M. | Liebow, Mark | Blair, Aaron | Cantor, Kenneth P. | Kane, Eleanor V. | Lightfoot, Tracy | Roman, Eve | Smith, Alex | Brooks-Wilson, Angela | Connors, Joseph M. | Gascoyne, Randy D. | Spinelli, John J. | Armstrong, Bruce K. | Kricker, Anne | Holford, Theodore R. | Lan, Qing | Zheng, Tongzhang | Orsi, Laurent | Dal Maso, Luigino | Franceschi, Silvia | La Vecchia, Carlo | Negri, Eva | Serraino, Diego | Bernstein, Leslie | Levine, Alexandra | Friedberg, Jonathan W. | Kelly, Jennifer L. | Berndt, Sonja I. | Birmann, Brenda M. | Clarke, Christina A. | Flowers, Christopher R. | Foran, James M. | Kadin, Marshall E. | Paltiel, Ora | Weisenburger, Dennis D. | Linet, Martha S. | Sampson, Joshua N.
Background
Non-Hodgkin lymphoma (NHL) comprises biologically and clinically heterogeneous subtypes. Previously, study size has limited the ability to compare and contrast the risk factor profiles among these heterogeneous subtypes.
Methods
We pooled individual-level data from 17 471 NHL cases and 23 096 controls in 20 case–control studies from the International Lymphoma Epidemiology Consortium (InterLymph). We estimated the associations, measured as odds ratios, between each of 11 NHL subtypes and self-reported medical history, family history of hematologic malignancy, lifestyle factors, and occupation. We then assessed the heterogeneity of associations by evaluating the variability (Q value) of the estimated odds ratios for a given exposure among subtypes. Finally, we organized the subtypes into a hierarchical tree to identify groups that had similar risk factor profiles. Statistical significance of tree partitions was estimated by permutation-based P values (P NODE).
Results
Risks differed statistically significantly among NHL subtypes for medical history factors (autoimmune diseases, hepatitis C virus seropositivity, eczema, and blood transfusion), family history of leukemia and multiple myeloma, alcohol consumption, cigarette smoking, and certain occupations, whereas generally homogeneous risks among subtypes were observed for family history of NHL, recreational sun exposure, hay fever, allergy, and socioeconomic status. Overall, the greatest difference in risk factors occurred between T-cell and B-cell lymphomas (P NODE < 1.0×10−4), with increased risks generally restricted to T-cell lymphomas for eczema, T-cell-activating autoimmune diseases, family history of multiple myeloma, and occupation as a painter. We further observed substantial heterogeneity among B-cell lymphomas (P NODE < 1.0×10−4). Increased risks for B-cell-activating autoimmune disease and hepatitis C virus seropositivity and decreased risks for alcohol consumption and occupation as a teacher generally were restricted to marginal zone lymphoma, Burkitt/Burkitt-like lymphoma/leukemia, diffuse large B-cell lymphoma, and/or lymphoplasmacytic lymphoma/Waldenström macroglobulinemia.
Conclusions
Using a novel approach to investigate etiologic heterogeneity among NHL subtypes, we identified risk factors that were common among subtypes as well as risk factors that appeared to be distinct among individual or a few subtypes, suggesting both subtype-specific and shared underlying mechanisms. Further research is needed to test putative mechanisms, investigate other risk factors (eg, other infections, environmental exposures, and diet), and evaluate potential joint effects with genetic susceptibility.
doi:10.1093/jncimonographs/lgu013
PMCID: PMC4155467  PMID: 25174034
3.  A genome-wide association study of marginal zone lymphoma shows association to the HLA region 
Vijai, Joseph | Wang, Zhaoming | Berndt, Sonja I | Skibola, Christine F | Slager, Susan L | de Sanjose, Silvia | Melbye, Mads | Glimelius, Bengt | Bracci, Paige M | Conde, Lucia | Birmann, Brenda M | Wang, Sophia S | Brooks-Wilson, Angela R | Lan, Qing | de Bakker, Paul I W | Vermeulen, Roel C H | Portlock, Carol | Ansell, Stephen M | Link, Brian K | Riby, Jacques | North, Kari E | Gu, Jian | Hjalgrim, Henrik | Cozen, Wendy | Becker, Nikolaus | Teras, Lauren R | Spinelli, John J | Turner, Jenny | Zhang, Yawei | Purdue, Mark P | Giles, Graham G | Kelly, Rachel S | Zeleniuch-Jacquotte, Anne | Ennas, Maria Grazia | Monnereau, Alain | Bertrand, Kimberly A | Albanes, Demetrius | Lightfoot, Tracy | Yeager, Meredith | Chung, Charles C | Burdett, Laurie | Hutchinson, Amy | Lawrence, Charles | Montalvan, Rebecca | Liang, Liming | Huang, Jinyan | Ma, Baoshan | Villano, Danylo J | Maria, Ann | Corines, Marina | Thomas, Tinu | Novak, Anne J | Dogan, Ahmet | Liebow, Mark | Thompson, Carrie A | Witzig, Thomas E | Habermann, Thomas M | Weiner, George J | Smith, Martyn T | Holly, Elizabeth A | Jackson, Rebecca D | Tinker, Lesley F | Ye, Yuanqing | Adami, Hans-Olov | Smedby, Karin E | De Roos, Anneclaire J | Hartge, Patricia | Morton, Lindsay M | Severson, Richard K | Benavente, Yolanda | Boffetta, Paolo | Brennan, Paul | Foretova, Lenka | Maynadie, Marc | McKay, James | Staines, Anthony | Diver, W Ryan | Vajdic, Claire M | Armstrong, Bruce K | Kricker, Anne | Zheng, Tongzhang | Holford, Theodore R | Severi, Gianluca | Vineis, Paolo | Ferri, Giovanni M | Ricco, Rosalia | Miligi, Lucia | Clavel, Jacqueline | Giovannucci, Edward | Kraft, Peter | Virtamo, Jarmo | Smith, Alex | Kane, Eleanor | Roman, Eve | Chiu, Brian C H | Fraumeni, Joseph F | Wu, Xifeng | Cerhan, James R | Offit, Kenneth | Chanock, Stephen J | Rothman, Nathaniel | Nieters, Alexandra
Nature communications  2015;6:5751.
Marginal zone lymphoma (MZL) is the third most common subtype of B-cell non-Hodgkin lymphoma. Here we perform a two-stage GWAS of 1,281 MZL cases and 7,127 controls of European ancestry and identify two independent loci near BTNL2 (rs9461741, P=3.95×10−15) and HLA-B (rs2922994, P=2.43×10−9) in the HLA region significantly associated with MZL risk. This is the first evidence that genetic variation in the major histocompatibility complex influences MZL susceptibility.
doi:10.1038/ncomms6751
PMCID: PMC4287989  PMID: 25569183
5.  IARC Monographs: 40 Years of Evaluating Carcinogenic Hazards to Humans 
Pearce, Neil | Blair, Aaron | Vineis, Paolo | Ahrens, Wolfgang | Andersen, Aage | Anto, Josep M. | Armstrong, Bruce K. | Baccarelli, Andrea A. | Beland, Frederick A. | Berrington, Amy | Bertazzi, Pier Alberto | Birnbaum, Linda S. | Brownson, Ross C. | Bucher, John R. | Cantor, Kenneth P. | Cardis, Elisabeth | Cherrie, John W. | Christiani, David C. | Cocco, Pierluigi | Coggon, David | Comba, Pietro | Demers, Paul A. | Dement, John M. | Douwes, Jeroen | Eisen, Ellen A. | Engel, Lawrence S. | Fenske, Richard A. | Fleming, Lora E. | Fletcher, Tony | Fontham, Elizabeth | Forastiere, Francesco | Frentzel-Beyme, Rainer | Fritschi, Lin | Gerin, Michel | Goldberg, Marcel | Grandjean, Philippe | Grimsrud, Tom K. | Gustavsson, Per | Haines, Andy | Hartge, Patricia | Hansen, Johnni | Hauptmann, Michael | Heederik, Dick | Hemminki, Kari | Hemon, Denis | Hertz-Picciotto, Irva | Hoppin, Jane A. | Huff, James | Jarvholm, Bengt | Kang, Daehee | Karagas, Margaret R. | Kjaerheim, Kristina | Kjuus, Helge | Kogevinas, Manolis | Kriebel, David | Kristensen, Petter | Kromhout, Hans | Laden, Francine | Lebailly, Pierre | LeMasters, Grace | Lubin, Jay H. | Lynch, Charles F. | Lynge, Elsebeth | ‘t Mannetje, Andrea | McMichael, Anthony J. | McLaughlin, John R. | Marrett, Loraine | Martuzzi, Marco | Merchant, James A. | Merler, Enzo | Merletti, Franco | Miller, Anthony | Mirer, Franklin E. | Monson, Richard | Nordby, Karl-Cristian | Olshan, Andrew F. | Parent, Marie-Elise | Perera, Frederica P. | Perry, Melissa J. | Pesatori, Angela Cecilia | Pirastu, Roberta | Porta, Miquel | Pukkala, Eero | Rice, Carol | Richardson, David B. | Ritter, Leonard | Ritz, Beate | Ronckers, Cecile M. | Rushton, Lesley | Rusiecki, Jennifer A. | Rusyn, Ivan | Samet, Jonathan M. | Sandler, Dale P. | de Sanjose, Silvia | Schernhammer, Eva | Costantini, Adele Seniori | Seixas, Noah | Shy, Carl | Siemiatycki, Jack | Silverman, Debra T. | Simonato, Lorenzo | Smith, Allan H. | Smith, Martyn T. | Spinelli, John J. | Spitz, Margaret R. | Stallones, Lorann | Stayner, Leslie T. | Steenland, Kyle | Stenzel, Mark | Stewart, Bernard W. | Stewart, Patricia A. | Symanski, Elaine | Terracini, Benedetto | Tolbert, Paige E. | Vainio, Harri | Vena, John | Vermeulen, Roel | Victora, Cesar G. | Ward, Elizabeth M. | Weinberg, Clarice R. | Weisenburger, Dennis | Wesseling, Catharina | Weiderpass, Elisabete | Zahm, Shelia Hoar
Environmental Health Perspectives  2015;123(6):507-514.
Background: Recently, the International Agency for Research on Cancer (IARC) Programme for the Evaluation of Carcinogenic Risks to Humans has been criticized for several of its evaluations, and also for the approach used to perform these evaluations. Some critics have claimed that failures of IARC Working Groups to recognize study weaknesses and biases of Working Group members have led to inappropriate classification of a number of agents as carcinogenic to humans.
Objectives: The authors of this Commentary are scientists from various disciplines relevant to the identification and hazard evaluation of human carcinogens. We examined criticisms of the IARC classification process to determine the validity of these concerns. Here, we present the results of that examination, review the history of IARC evaluations, and describe how the IARC evaluations are performed.
Discussion: We concluded that these recent criticisms are unconvincing. The procedures employed by IARC to assemble Working Groups of scientists from the various disciplines and the techniques followed to review the literature and perform hazard assessment of various agents provide a balanced evaluation and an appropriate indication of the weight of the evidence. Some disagreement by individual scientists to some evaluations is not evidence of process failure. The review process has been modified over time and will undoubtedly be altered in the future to improve the process. Any process can in theory be improved, and we would support continued review and improvement of the IARC processes. This does not mean, however, that the current procedures are flawed.
Conclusions: The IARC Monographs have made, and continue to make, major contributions to the scientific underpinning for societal actions to improve the public’s health.
Citation: Pearce N, Blair A, Vineis P, Ahrens W, Andersen A, Anto JM, Armstrong BK, Baccarelli AA, Beland FA, Berrington A, Bertazzi PA, Birnbaum LS, Brownson RC, Bucher JR, Cantor KP, Cardis E, Cherrie JW, Christiani DC, Cocco P, Coggon D, Comba P, Demers PA, Dement JM, Douwes J, Eisen EA, Engel LS, Fenske RA, Fleming LE, Fletcher T, Fontham E, Forastiere F, Frentzel-Beyme R, Fritschi L, Gerin M, Goldberg M, Grandjean P, Grimsrud TK, Gustavsson P, Haines A, Hartge P, Hansen J, Hauptmann M, Heederik D, Hemminki K, Hemon D, Hertz-Picciotto I, Hoppin JA, Huff J, Jarvholm B, Kang D, Karagas MR, Kjaerheim K, Kjuus H, Kogevinas M, Kriebel D, Kristensen P, Kromhout H, Laden F, Lebailly P, LeMasters G, Lubin JH, Lynch CF, Lynge E, ‘t Mannetje A, McMichael AJ, McLaughlin JR, Marrett L, Martuzzi M, Merchant JA, Merler E, Merletti F, Miller A, Mirer FE, Monson R, Nordby KC, Olshan AF, Parent ME, Perera FP, Perry MJ, Pesatori AC, Pirastu R, Porta M, Pukkala E, Rice C, Richardson DB, Ritter L, Ritz B, Ronckers CM, Rushton L, Rusiecki JA, Rusyn I, Samet JM, Sandler DP, de Sanjose S, Schernhammer E, Seniori Costantini A, Seixas N, Shy C, Siemiatycki J, Silverman DT, Simonato L, Smith AH, Smith MT, Spinelli JJ, Spitz MR, Stallones L, Stayner LT, Steenland K, Stenzel M, Stewart BW, Stewart PA, Symanski E, Terracini B, Tolbert PE, Vainio H, Vena J, Vermeulen R, Victora CG, Ward EM, Weinberg CR, Weisenburger D, Wesseling C, Weiderpass E, Zahm SH. 2015. IARC Monographs: 40 years of evaluating carcinogenic hazards to humans. Environ Health Perspect 123:507–514; http://dx.doi.org/10.1289/ehp.1409149
doi:10.1289/ehp.1409149
PMCID: PMC4455595  PMID: 25712798
6.  Genome-wide association study identifies multiple susceptibility loci for diffuse large B-cell lymphoma 
Cerhan, James R | Berndt, Sonja I | Vijai, Joseph | Ghesquières, Hervé | McKay, James | Wang, Sophia S | Wang, Zhaoming | Yeager, Meredith | Conde, Lucia | de Bakker, Paul I W | Nieters, Alexandra | Cox, David | Burdett, Laurie | Monnereau, Alain | Flowers, Christopher R | De Roos, Anneclaire J | Brooks-Wilson, Angela R | Lan, Qing | Severi, Gianluca | Melbye, Mads | Gu, Jian | Jackson, Rebecca D | Kane, Eleanor | Teras, Lauren R | Purdue, Mark P | Vajdic, Claire M | Spinelli, John J | Giles, Graham G | Albanes, Demetrius | Kelly, Rachel S | Zucca, Mariagrazia | Bertrand, Kimberly A | Zeleniuch-Jacquotte, Anne | Lawrence, Charles | Hutchinson, Amy | Zhi, Degui | Habermann, Thomas M | Link, Brian K | Novak, Anne J | Dogan, Ahmet | Asmann, Yan W | Liebow, Mark | Thompson, Carrie A | Ansell, Stephen M | Witzig, Thomas E | Weiner, George J | Veron, Amelie S | Zelenika, Diana | Tilly, Hervé | Haioun, Corinne | Molina, Thierry Jo | Hjalgrim, Henrik | Glimelius, Bengt | Adami, Hans-Olov | Bracci, Paige M | Riby, Jacques | Smith, Martyn T | Holly, Elizabeth A | Cozen, Wendy | Hartge, Patricia | Morton, Lindsay M | Severson, Richard K | Tinker, Lesley F | North, Kari E | Becker, Nikolaus | Benavente, Yolanda | Boffetta, Paolo | Brennan, Paul | Foretova, Lenka | Maynadie, Marc | Staines, Anthony | Lightfoot, Tracy | Crouch, Simon | Smith, Alex | Roman, Eve | Diver, W Ryan | Offit, Kenneth | Zelenetz, Andrew | Klein, Robert J | Villano, Danylo J | Zheng, Tongzhang | Zhang, Yawei | Holford, Theodore R | Kricker, Anne | Turner, Jenny | Southey, Melissa C | Clavel, Jacqueline | Virtamo, Jarmo | Weinstein, Stephanie | Riboli, Elio | Vineis, Paolo | Kaaks, Rudolph | Trichopoulos, Dimitrios | Vermeulen, Roel C H | Boeing, Heiner | Tjonneland, Anne | Angelucci, Emanuele | Di Lollo, Simonetta | Rais, Marco | Birmann, Brenda M | Laden, Francine | Giovannucci, Edward | Kraft, Peter | Huang, Jinyan | Ma, Baoshan | Ye, Yuanqing | Chiu, Brian C H | Sampson, Joshua | Liang, Liming | Park, Ju-Hyun | Chung, Charles C | Weisenburger, Dennis D | Chatterjee, Nilanjan | Fraumeni, Joseph F | Slager, Susan L | Wu, Xifeng | de Sanjose, Silvia | Smedby, Karin E | Salles, Gilles | Skibola, Christine F | Rothman, Nathaniel | Chanock, Stephen J
Nature genetics  2014;46(11):1233-1238.
doi:10.1038/ng.3105
PMCID: PMC4213349  PMID: 25261932
7.  Vitamin D Metabolic Pathway Genes and Pancreatic Cancer Risk 
PLoS ONE  2015;10(3):e0117574.
Evidence on the association between vitamin D status and pancreatic cancer risk is inconsistent. This inconsistency may be partially attributable to variation in vitamin D regulating genes. We selected 11 vitamin D-related genes (GC, DHCR7, CYP2R1, VDR, CYP27B1, CYP24A1, CYP27A1, RXRA, CRP2, CASR and CUBN) totaling 213 single nucleotide polymorphisms (SNPs), and examined associations with pancreatic adenocarcinoma. Our study included 3,583 pancreatic cancer cases and 7,053 controls from the genome-wide association studies of pancreatic cancer PanScans-I-III. We used the Adaptive Joint Test and the Adaptive Rank Truncated Product statistic for pathway and gene analyses, and unconditional logistic regression for SNP analyses, adjusting for age, sex, study and population stratification. We examined effect modification by circulating vitamin D concentration (≤50, >50 nmol/L) for the most significant SNPs using a subset of cohort cases (n = 713) and controls (n = 878). The vitamin D metabolic pathway was not associated with pancreatic cancer risk (p = 0.830). Of the individual genes, none were associated with pancreatic cancer risk at a significance level of p<0.05. SNPs near the VDR (rs2239186), LRP2 (rs4668123), CYP24A1 (rs2762932), GC (rs2282679), and CUBN (rs1810205) genes were the top SNPs associated with pancreatic cancer (p-values 0.008–0.037), but none were statistically significant after adjusting for multiple comparisons. Associations between these SNPs and pancreatic cancer were not modified by circulating concentrations of vitamin D. These findings do not support an association between vitamin D-related genes and pancreatic cancer risk. Future research should explore other pathways through which vitamin D status might be associated with pancreatic cancer risk.
doi:10.1371/journal.pone.0117574
PMCID: PMC4370655  PMID: 25799011
8.  Body Mass Index and Risk of Death in Asian Americans 
American journal of public health  2014;104(3):520-525.
Objective
To investigate the association between body mass index (BMI) and mortality among Asian Americans
Methods
We pooled data from prospective cohort studies that included 20,672 Asian American adults with no history of cancer or heart disease at baseline. Hazard ratios and 95% confidence intervals (CI) were estimated using Cox proportional hazards models.
Results
A high, but not low, BMI was associated with an increased risk of total mortality among individuals 35–69 years old. BMI was not related to total mortality among individuals ≥70 years old. With a BMI 22.5–<25 as the reference category among 35–69 year old never smokers the hazard ratios (95% CI) for total mortality were 0.83 (0.47–1.47) for BMI 15–<18.5, 0.91 (0.62–1.32) for BMI 18.5–<20, 1.08 (0.86–1.36) for BMI 20–<22.5, 1.14 (0.90–1.44) for BMI 25–<27.5, 1.13 (0.79–1.62) for BMI 27.5–<30, 1.82 (1.25–2.64) for BMI 30–<35, and 2.09 (1.06–4.11) for BMI 35–50. Higher BMI was also related to an increased mortality from cardiovascular disease and cancer.
Conclusions
A high BMI is associated with increased risk of mortality among Asian Americans.
doi:10.2105/AJPH.2013.301573
PMCID: PMC3953786  PMID: 24432919
9.  A Pooled Analysis of Waist Circumference and Mortality in 650,000 Adults 
Mayo Clinic proceedings  2014;89(3):335-345.
Objective
To assess the independent impact of waist circumference on mortality across the entire range of body mass index (BMI), and to estimate the loss in life expectancy related to a higher waist circumference.
Methods
We pooled data from 11 prospective cohort studies with 650,386 white adults aged 20–83 years and enrolled from January 1, 1986 through December 31, 2000. We used proportional hazards regression to estimate hazard ratios (HR) and 95% confidence intervals (95%CI) for the association of waist circumference with mortality.
Results
During a median follow-up of 9 years (maximum=21 years), 78,268 participants died. After accounting for age, study, BMI, smoking status, alcohol consumption, and physical activity, there was a strong positive linear association of waist circumference with all-cause mortality was observed for men (HR=1.52 for 110+ versus <90cm, 95%CI, 1.45–1.59; HR=1.07 per 5cm increment, 95%CI, 1.06–1.08) and women (HR=1.80 for 95+ versus <70cm, 95%CI, 1.70–1.89; HR=1.09 per 5cm increment, 95%CI, 1.08–1.09). The estimated decrease in life expectancy for highest versus lowest waist circumference was ~3 years for men and ~5 years for women. The HR per 5cm increment in waist circumference was similar for both sexes at all BMI levels from 20–50 kg/m2, but it was higher at younger ages, higher for longer follow-up, and lower among male current smokers. The associations were stronger for heart and respiratory disease mortality than for cancer.
Conclusions
In white adults, higher waist circumference was positively associated with higher mortality at all levels of BMI from 20–50 kg/m2. Waist circumference should be assessed in combination with BMI, even for those in the normal BMI range, as part of risk assessment for obesity-related premature mortality.
doi:10.1016/j.mayocp.2013.11.011
PMCID: PMC4104704  PMID: 24582192
10.  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
11.  A genome-wide association study of marginal zone lymphoma shows association to the HLA region 
Vijai, Joseph | Wang, Zhaoming | Berndt, Sonja I. | Skibola, Christine F. | Slager, Susan L. | de Sanjose, Silvia | Melbye, Mads | Glimelius, Bengt | Bracci, Paige M. | Conde, Lucia | Birmann, Brenda M. | Wang, Sophia S. | Brooks-Wilson, Angela R. | Lan, Qing | de Bakker, Paul I. W. | Vermeulen, Roel C. H. | Portlock, Carol | Ansell, Stephen M. | Link, Brian K. | Riby, Jacques | North, Kari E. | Gu, Jian | Hjalgrim, Henrik | Cozen, Wendy | Becker, Nikolaus | Teras, Lauren R. | Spinelli, John J. | Turner, Jenny | Zhang, Yawei | Purdue, Mark P. | Giles, Graham G. | Kelly, Rachel S. | Zeleniuch-Jacquotte, Anne | Ennas, Maria Grazia | Monnereau, Alain | Bertrand, Kimberly A. | Albanes, Demetrius | Lightfoot, Tracy | Yeager, Meredith | Chung, Charles C. | Burdett, Laurie | Hutchinson, Amy | Lawrence, Charles | Montalvan, Rebecca | Liang, Liming | Huang, Jinyan | Ma, Baoshan | Villano, Danylo J. | Maria, Ann | Corines, Marina | Thomas, Tinu | Novak, Anne J. | Dogan, Ahmet | Liebow, Mark | Thompson, Carrie A. | Witzig, Thomas E. | Habermann, Thomas M. | Weiner, George J. | Smith, Martyn T. | Holly, Elizabeth A. | Jackson, Rebecca D. | Tinker, Lesley F. | Ye, Yuanqing | Adami, Hans-Olov | Smedby, Karin E. | De Roos, Anneclaire J. | Hartge, Patricia | Morton, Lindsay M. | Severson, Richard K. | Benavente, Yolanda | Boffetta, Paolo | Brennan, Paul | Foretova, Lenka | Maynadie, Marc | McKay, James | Staines, Anthony | Diver, W. Ryan | Vajdic, Claire M. | Armstrong, Bruce K. | Kricker, Anne | Zheng, Tongzhang | Holford, Theodore R. | Severi, Gianluca | Vineis, Paolo | Ferri, Giovanni M. | Ricco, Rosalia | Miligi, Lucia | Clavel, Jacqueline | Giovannucci, Edward | Kraft, Peter | Virtamo, Jarmo | Smith, Alex | Kane, Eleanor | Roman, Eve | Chiu, Brian C. H. | Fraumeni, Joseph F. | Wu, Xifeng | Cerhan, James R. | Offit, Kenneth | Chanock, Stephen J. | Rothman, Nathaniel | Nieters, Alexandra
Nature Communications  2015;6:5751.
Marginal zone lymphoma (MZL) is the third most common subtype of B-cell non-Hodgkin lymphoma. Here we perform a two-stage GWAS of 1,281 MZL cases and 7,127 controls of European ancestry and identify two independent loci near BTNL2 (rs9461741, P=3.95 × 10−15) and HLA-B (rs2922994, P=2.43 × 10−9) in the HLA region significantly associated with MZL risk. This is the first evidence that genetic variation in the major histocompatibility complex influences MZL susceptibility.
Marginal zone lymphoma (MZL) is a common subtype of B-cell non-Hodgkin lymphoma. Here the authors carry out a two-stage genome-wide association study in over 8,000 Europeans and identify two new MZL risk loci at chromosome 6p, implicating the major histocompatibility complex in the disease for the first time.
doi:10.1038/ncomms6751
PMCID: PMC4287989  PMID: 25569183
12.  Personal history of diabetes, genetic susceptibility to diabetes, and risk of brain glioma: a pooled analysis of observational studies 
Background
Brain glioma is a relatively rare and fatal malignancy in adulthood with few known risk factors. Some observational studies have reported inverse associations between diabetes and subsequent glioma risk, but possible mechanisms are unclear.
Methods
We conducted a pooled analysis of original data from five nested case-control studies and two case-control studies from the U.S. and China that included 962 glioma cases and 2,195 controls. We examined self-reported diabetes history in relation to glioma risk, as well as effect modification by seven glioma risk-associated single-nucleotide polymorphisms (SNPs). We also examined the associations between 13 diabetes risk-associated SNPs, identified from genome-wide association studies, and glioma risk. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using multivariable-adjusted logistic regression models.
Results
We observed a 42% reduced risk of glioma for individuals with a history of diabetes (OR=0.58, 95% CI: 0.40–0.84). The association did not differ by sex, study design, or after restricting to glioblastoma, the most common histological sub-type. We did not observe any significant per-allele trends among the 13 diabetes-related SNPs examined in relation to glioma risk.
Conclusion
These results support an inverse association between diabetes history and glioma risk. The role of genetic susceptibility to diabetes cannot be excluded, and should be pursued in future studies together with other factors that might be responsible for the diabetes-glioma association.
Impact
These data suggest the need for studies that can evaluate, separately, the association between type 1 and type 2 diabetes and subsequent risk of adult glioma.
doi:10.1158/1055-9965.EPI-13-0913
PMCID: PMC3947107  PMID: 24220915
diabetes mellitus; brain cancer; glioma; cancer; epidemiology
13.  A Pooled Analysis of Body Mass Index and Mortality among African Americans 
PLoS ONE  2014;9(11):e111980.
Pooled analyses among whites and East Asians have demonstrated positive associations between all-cause mortality and body mass index (BMI), but studies of African Americans have yielded less consistent results. We examined the association between BMI and all-cause mortality in a sample of African Americans pooled from seven prospective cohort studies: NIH-AARP, 1995–2009; Adventist Health Study 2, 2002–2008; Black Women's Health Study, 1995–2009; Cancer Prevention Study II, 1982–2008; Multiethnic Cohort Study, 1993–2007; Prostate, Lung, Colorectal and Ovarian Screening Trial, 1993–2009; Southern Community Cohort Study, 2002–2009. 239,526 African Americans (including 100,175 never smokers without baseline heart disease, stroke, or cancer), age 30–104 (mean 52) and 71% female, were followed up to 26.5 years (mean 11.7). Hazard ratios (HR) and 95% confidence intervals (CI) for mortality were derived from multivariate Cox proportional hazards models. Among healthy, never smokers (11,386 deaths), HRs (CI) for BMI 25–27.4, 27.5–29.9, 30–34.9, 35–39.9, 40–49.9, and 50–60 kg/m2 were 1.02 (0.92–1.12), 1.06 (0.95–1.18), 1.32 (1.18–1.47), 1.54 (1.29–1.83), 1.93 (1.46–2.56), and 1.93 (0.80–4.69), respectively among men and 1.06 (0.99–1.15), 1.15 (1.06–1.25), 1.24 (1.15–1.34), 1.58 (1.43–1.74), 1.80 (1.60–2.02), and 2.31 (1.74–3.07) respectively among women (reference category 22.5–24.9). HRs were highest among those with the highest educational attainment, longest follow-up, and for cardiovascular disease mortality. Obesity was associated with a higher risk of mortality in African Americans, similar to that observed in pooled analyses of whites and East Asians. This study provides compelling evidence to support public health efforts to prevent excess weight gain and obesity in African Americans.
doi:10.1371/journal.pone.0111980
PMCID: PMC4234271  PMID: 25401742
14.  Environmental determinants of polychlorinated biphenyl concentrations in residential carpet dust 
Environmental science & technology  2013;47(18):10405-10414.
Polychlorinated biphenyls (PCBs), banned in the United Sates in the late 1970s, are still found in indoor and outdoor environments. Little is known about the determinants of PCB levels in homes. We measured concentrations of 5 PCB congeners (105, 138, 153, 170, 180) in carpet dust collected between 1998–2000 from 1,187 homes in four sites: Detroit, Iowa, Los Angeles, and Seattle. Home characteristics, occupational history, and demographic information were obtained by interview. We used a geographic information system to geocode addresses and determine distances to the nearest major road, freight route, and railroad, percentage of developed land, number of industrial facilities within 2 km of residences, and population density. Ordinal logistic regression was used to estimate the associations between the covariates of interest and the odds of PCB detection in each site separately. Total PCBs levels (all congeners < maximum practical quantitation limit [MPQL] vs. at least one congener ≥ MPQL to < median concentration vs. at least one congener >median concentration) were positively associated with either percentage of developed land (ORrange: 1.01-1.04 for each percentage increase) or population density (OR: 1.08 for every 1,000/mi2) in each site. The number of industrial facilities within 2 km of a home was associated with PCB concentrations; however, facility type and the direction of the association varied by site. Our findings suggest that outdoor sources of PCBs may be significant determinants of indoor concentrations.
doi:10.1021/es401447w
PMCID: PMC4076890  PMID: 23952055
15.  Polymorphisms in genes related to one-carbon metabolism are not related to pancreatic cancer in PanScan and PanC4 
Cancer causes & control : CCC  2013;24(3):595-602.
Purpose
The evidence of a relation between folate intake and one-carbon metabolism (OCM) with pancreatic cancer (PanCa) is inconsistent. In this study, the association between genes and single-nucleotide polymorphisms (SNPs) related to OCM and PanCa was assessed.
Methods
Using biochemical knowledge of the OCM pathway, we identified thirty-seven genes and 834 SNPs to examine in association with PanCa. Our study included 1,408 cases and 1,463 controls nested within twelve cohorts (PanScan). The ten SNPs and five genes with lowest p values (<0.02) were followed up in 2,323 cases and 2,340 controls from eight case-control studies (PanC4) that participated in PanScan2. The correlation of SNPs with metabolite levels was assessed for 649 controls from the European Prospective Investigation into Cancer and Nutrition.
Results
When both stages were combined, we observed suggestive associations with PanCa for rs10887710 (MAT1A) (OR 1.13, 95%CI 1.04-1.23), rs1552462 (SYT9) (OR 1.27, 95%CI 1.02-1.59), and rs7074891 (CUBN) (OR 1.91, 95%CI 1.12-3.26). After correcting for multiple comparisons, no significant associations were observed in either the first or second stage. The three suggested SNPs showed no correlations with one-carbon biomarkers.
Conclusions
This is the largest genetic study to date to examine the relation between germline variations in OCM-related genes polymorphisms and the risk of PanCa. Suggestive evidence for an association between polymorphisms and PanCa was observed among the cohort-nested studies, but this did not replicate in the case-control studies. Our results do not strongly support the hypothesis that genes related to OCM play a role in pancreatic carcinogenesis.
doi:10.1007/s10552-012-0138-0
PMCID: PMC4127987  PMID: 23334854
Pancreatic cancer; One-carbon metabolism; Polymorphisms; Biomarkers; Epidemiology
16.  Cancer Screening: The Journey from Epidemiology to Policy 
Annals of epidemiology  2012;22(6):439-445.
Cancer screening procedures have brought great benefit to the public’s health. However, the science of cancer screening and the evidence arising from research in this field as it is applied to policy is complex and has been difficult to communicate, especially on the national stage. We explore how epidemiologists have contributed to this evidence base and to its translation into policy. Our essay focuses on breast and lung cancer screening to identify commonalities of experience by epidemiologists across two different cancer sites and describe how epidemiologists interact with evolving scientific and policy environments. We describe the roles and challenges that epidemiologists encounter according to the maturity of the data, stakeholders, and the related political context. We also explore the unique position of cancer screening as influenced by the legislative landscape where, due to recent healthcare reform, cancer screening research plays directly into national policy. In the complex landscape for cancer screening policy, epidemiologists can increase their impact by learning from past experiences, being well prepared and communicating effectively.
doi:10.1016/j.annepidem.2012.03.004
PMCID: PMC4096857  PMID: 22626002
Epidemiology; Public Policy; Health Policy; Cancer Screening
17.  Association between Class III Obesity (BMI of 40–59 kg/m2) and Mortality: A Pooled Analysis of 20 Prospective Studies 
PLoS Medicine  2014;11(7):e1001673.
In a pooled analysis of 20 prospective studies, Cari Kitahara and colleagues find that class III obesity (BMI of 40–59) is associated with excess rates of total mortality, particularly due to heart disease, cancer, and diabetes.
Please see later in the article for the Editors' Summary
Background
The prevalence of class III obesity (body mass index [BMI]≥40 kg/m2) has increased dramatically in several countries and currently affects 6% of adults in the US, with uncertain impact on the risks of illness and death. Using data from a large pooled study, we evaluated the risk of death, overall and due to a wide range of causes, and years of life expectancy lost associated with class III obesity.
Methods and Findings
In a pooled analysis of 20 prospective studies from the United States, Sweden, and Australia, we estimated sex- and age-adjusted total and cause-specific mortality rates (deaths per 100,000 persons per year) and multivariable-adjusted hazard ratios for adults, aged 19–83 y at baseline, classified as obese class III (BMI 40.0–59.9 kg/m2) compared with those classified as normal weight (BMI 18.5–24.9 kg/m2). Participants reporting ever smoking cigarettes or a history of chronic disease (heart disease, cancer, stroke, or emphysema) on baseline questionnaires were excluded. Among 9,564 class III obesity participants, mortality rates were 856.0 in men and 663.0 in women during the study period (1976–2009). Among 304,011 normal-weight participants, rates were 346.7 and 280.5 in men and women, respectively. Deaths from heart disease contributed largely to the excess rates in the class III obesity group (rate differences = 238.9 and 132.8 in men and women, respectively), followed by deaths from cancer (rate differences = 36.7 and 62.3 in men and women, respectively) and diabetes (rate differences = 51.2 and 29.2 in men and women, respectively). Within the class III obesity range, multivariable-adjusted hazard ratios for total deaths and deaths due to heart disease, cancer, diabetes, nephritis/nephrotic syndrome/nephrosis, chronic lower respiratory disease, and influenza/pneumonia increased with increasing BMI. Compared with normal-weight BMI, a BMI of 40–44.9, 45–49.9, 50–54.9, and 55–59.9 kg/m2 was associated with an estimated 6.5 (95% CI: 5.7–7.3), 8.9 (95% CI: 7.4–10.4), 9.8 (95% CI: 7.4–12.2), and 13.7 (95% CI: 10.5–16.9) y of life lost. A limitation was that BMI was mainly ascertained by self-report.
Conclusions
Class III obesity is associated with substantially elevated rates of total mortality, with most of the excess deaths due to heart disease, cancer, and diabetes, and major reductions in life expectancy compared with normal weight.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The number of obese people (individuals with an excessive amount of body fat) is increasing rapidly in many countries. Worldwide, according to the Global Burden of Disease Study 2013, more than a third of all adults are now overweight or obese. Obesity is defined as having a body mass index (BMI, an indicator of body fat calculated by dividing a person's weight in kilograms by their height in meters squared) of more than 30 kg/m2 (a 183-cm [6-ft] tall man who weighs more than 100 kg [221 lbs] is obese). Compared to people with a healthy weight (a BMI between 18.5 and 24.9 kg/m2), overweight and obese individuals (who have a BMI between 25.0 and 29.9 kg/m2 and a BMI of 30 kg/m2 or more, respectively) have an increased risk of developing diabetes, heart disease, stroke, and some cancers, and tend to die younger. Because people become unhealthily fat by consuming food and drink that contains more energy (kilocalories) than they need for their daily activities, obesity can be prevented or treated by eating less food and by increasing physical activity.
Why Was This Study Done?
Class III obesity (extreme, or morbid, obesity), which is defined as a BMI of more than 40 kg/m2, is emerging as a major public health problem in several high-income countries. In the US, for example, 6% of adults are now morbidly obese. Because extreme obesity used to be relatively uncommon, little is known about the burden of disease, including total and cause-specific mortality (death) rates, among individuals with class III obesity. Before we can prevent and treat class III obesity effectively, we need a better understanding of the health risks associated with this condition. In this pooled analysis of prospective cohort studies, the researchers evaluate the risk of total and cause-specific death and the years of life lost associated with class III obesity. A pooled analysis analyzes the data from several studies as if the data came from one large study; prospective cohort studies record the characteristics of a group of participants at baseline and follow them to see which individuals develop a specific condition.
What Did the Researchers Do and Find?
The researchers included 20 prospective (mainly US) cohort studies from the National Cancer Institute Cohort Consortium (a partnership that studies cancer by undertaking large-scale collaborations) in their pooled analysis. After excluding individuals who had ever smoked and people with a history of chronic disease, the analysis included 9,564 adults who were classified as class III obese based on self-reported height and weight at baseline and 304,011 normal-weight adults. Among the participants with class III obesity, mortality rates (deaths per 100,000 persons per year) during the 30-year study period were 856.0 and 663.0 in men and women, respectively, whereas the mortality rates among normal-weight men and women were 346.7 and 280.5, respectively. Heart disease was the major contributor to the excess death rate among individuals with class III obesity, followed by cancer and diabetes. Statistical analyses of the pooled data indicate that the risk of all-cause death and death due to heart disease, cancer, diabetes, and several other diseases increased with increasing BMI. Finally, compared with having a normal weight, having a BMI between 40 and 59 kg/m2 resulted in an estimated loss of 6.5 to 13.7 years of life.
What Do These Findings Mean?
These findings indicate that class III obesity is associated with a substantially increased rate of death. Notably, this death rate increase is similar to the increase associated with smoking among normal-weight people. The findings also suggest that heart disease, cancer, and diabetes are responsible for most of the excess deaths among people with class III obesity and that having class III obesity results in major reductions in life expectancy. Importantly, the number of years of life lost continues to increase for BMI values above 50 kg/m2, and beyond this point, the loss of life expectancy exceeds that associated with smoking among normal-weight people. The accuracy of these findings is limited by the use of self-reported height and weight measurements to calculate BMI and by the use of BMI as the sole measure of obesity. Moreover, these findings may not be generalizable to all populations. Nevertheless, these findings highlight the need to develop more effective interventions to combat the growing public health problem of class III obesity.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001673.
The US Centers for Disease Control and Prevention provides information on all aspects of overweight and obesity (in English and Spanish)
The World Health Organization provides information on obesity (in several languages); Malri's story describes the health risks faced by an obese child
The UK National Health Service Choices website provides information about obesity, including a personal story about losing weight
The Global Burden of Disease Study website provides the latest details about global obesity trends
The US Department of Agriculture's ChooseMyPlate.gov website provides a personal healthy eating plan; the Weight-Control Information Network is an information service provided for the general public and health professionals by the US National Institute of Diabetes and Digestive and Kidney Diseases (in English and Spanish)
MedlinePlus provides links to other sources of information on obesity (in English and Spanish)
doi:10.1371/journal.pmed.1001673
PMCID: PMC4087039  PMID: 25003901
18.  Joint effects between five identified risk variants, allergy, and autoimmune conditions on glioma risk 
Cancer causes & control : CCC  2013;24(10):1885-1891.
Common variants in two of the five genetic regions recently identified from genome-wide association studies (GWAS) of risk of glioma were reported to interact with a history of allergic symptoms. In a pooled analysis of five epidemiologic studies, we evaluated the association between the five GWAS implicated gene variants and allergies and autoimmune conditions (AIC) on glioma risk (851 adult glioma cases and 3,977 controls). We further evaluated the joint effects between allergies and AIC and these gene variants on glioma risk. Risk estimates were calculated as odds ratios (OR) and 95 % confidence intervals (95 % CI), adjusted for age, gender, and study. Joint effects were evaluated by conducting stratified analyses whereby the risk associations (OR and 95 % CI) with the allergy or autoimmune conditions for glioma were evaluated by the presence or absence of the ‘at-risk’ variant, and estimated p interaction by fitting models with the main effects of allergy or autoimmune conditions and genotype and an interaction (product) term between them. Four of the five SNPs previously reported by others were statistically significantly associated with increased risk of glioma in our study (rs2736100, rs4295627, rs4977756, and rs6010620); rs498872 was not associated with glioma in our study. Reporting any allergies or AIC was associated with reduced risks of glioma (allergy: adjusted OR = 0.71, 95 % CI 0.55–0.91; AIC: adjusted OR = 0.65, 95 % CI 0.47–0.90). We did not observe differential association between allergic or autoimmune conditions and glioma by genotype, and there were no statistically significant p interactions. Stratified analysis by glioma grade (low and high grade) did not suggest risk differences by disease grade. Our results do not provide evidence that allergies or AIC modulate the association between the four GWAS-identified SNPs examined and risk of glioma.
doi:10.1007/s10552-013-0244-7
PMCID: PMC4074857  PMID: 23903690
Single-nucleotide polymorphisms; Glioma; Allergies; Autoimmune conditions; Gene–environment interaction
19.  The Epidemic of Non-Hodgkin Lymphoma in the United States: Disentangling the Effect of HIV, 1992–2009 
Background
For decades, non-Hodgkin lymphoma (NHL) incidence has been increasing worldwide. NHL risk is strongly increased among HIV-infected people. Our understanding of trends in NHL incidence has been hampered by difficulties in separating HIV-infected NHL cases from general population rates.
Materials and Methods
NHL incidence data during 1992–2009 were derived from 10 U.S. SEER cancer registries with information on HIV status at NHL diagnosis. The CDC estimated the number of people living with HIV in the registry areas. The proportion of NHL cases with HIV and NHL rates in the total and the HIV-uninfected populations were estimated. Time trends were assessed with Joinpoint analyses.
Results
Of 115,643 NHL cases diagnosed during 1992–2009, 5.9% were HIV-infected. The proportions of NHL cases with HIV were highest for diffuse large B-cell (DLBCL; 7.8%), Burkitt (26.9%), and peripheral T-cell lymphomas (3.2%) with low proportions (≤1.1%) in the other subtypes. NHL rates in the total population increased 0.3% per year during 1992–2009. However, rates of NHL in HIV-uninfected people increased 1.4% per year during 1992–2003, before becoming stable through 2009. Similar trends were observed for DLBCL and follicular lymphoma in HIV-uninfected people; rates increased 2.7% per year until 2003 and 1.7% per year until 2005, respectively, before stabilizing.
Conclusions
NHL incidence rates in the U.S. have plateaued over the last 5–10 years, independent of HIV infection.
Impact
Though the causes of the long-term increase in NHL incidence rates in the U.S. remain unknown, general population rates of NHL have stabilized since the early 2000s, independent of HIV.
doi:10.1158/1055-9965.EPI-13-0040
PMCID: PMC3698875  PMID: 23595542
non-Hodgkin lymphoma; HIV; trends
20.  Personal Use of Hair Dye and the Risk of Certain Subtypes of Non-Hodgkin Lymphoma 
American journal of epidemiology  2008;167(11):1321-1331.
Personal use of hair dye has been inconsistently linked to risk of non-Hodgkin lymphoma (NHL), perhaps because of small samples or a lack of detailed information on personal hair-dye use in previous studies. This study included 4,461 NHL cases and 5,799 controls from the International Lymphoma Epidemiology Consortium 1988–2003. Increased risk of NHL (odds ratio (OR) = 1.3, 95% confidence interval (CI): 1.1, 1.4) associated with hair-dye use was observed among women who began using hair dye before 1980. Analyses by NHL subtype showed increased risk for follicular lymphoma (FL) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) but not for other NHL subtypes. The increased risks of FL (OR = 1.4, 95% CI: 1.1, 1.9) and CLL/SLL (OR = 1.5, 95% CI: 1.1, 2.0) were mainly observed among women who started using hair dyes before 1980. For women who began using hair dye in 1980 or afterward, increased FL risk was limited to users of dark-colored dyes (OR = 1.5, 95% CI: 1.1, 2.0). These results indicate that personal hair-dye use may play a role in risks of FL and CLL/SLL in women who started use before 1980 and that increased risk of FL among women who started use during or after 1980 cannot be excluded.
doi:10.1093/aje/kwn058
PMCID: PMC4025953  PMID: 18408225
case-control studies; hair dyes; lymphoma; non-Hodgkin
21.  Known glioma risk loci are associated with glioma with a family history of brain tumours - a case-control gene association study 
Familial cancer can be used to leverage genetic association studies. Recent genome-wide association studies have reported independent associations between seven single nucleotide polymorphisms (SNPs) and risk of glioma. The aim of this study was to investigate whether glioma cases with a positive family history of brain tumours, defined as having at least one first or second degree relative with a history of brain tumour, are associated with known glioma risk loci. 1431 glioma cases and 2868 cancer-free controls were identified from four case-control studies and two prospective cohorts from USA, Sweden, and Denmark and genotyped for seven SNPs previously reported to be associated with glioma risk in case-control designed studies. Odds ratios were calculated by unconditional logistic regression. In analyses including glioma cases with a family history of brain tumours (n=104) and control subjects free of glioma at baseline, three out of seven SNPs were associated with glioma risk; rs2736100 (5p15.33, TERT), rs4977756 (9p21.3, CDKN2A-CDKN2B), and rs6010620 (20q13.33, RTEL1). After Bonferroni correction for multiple comparisons, only one marker was statistically significantly associated with glioma risk, rs6010620 (ORtrend for the minor (A) allele, 0.39; 95% CI, 0.25–0.61; Bonferroni adjusted ptrend, 1.7×10−4). In conclusion, as previously shown for glioma regardless of family history of brain tumours, rs6010620 (RTEL1) was associated with an increased risk of glioma when restricting to cases with family history of brain tumours. These findings require confirmation in further studies with a larger number of glioma cases with a family history of brain tumours.
doi:10.1002/ijc.27922
PMCID: PMC3586297  PMID: 23115063
Glioma; brain tumours; genome-wide association study; single nucleotide polymorphism
22.  Exome-Wide Association Study of Endometrial Cancer in a Multiethnic Population 
PLoS ONE  2014;9(5):e97045.
Endometrial cancer (EC) contributes substantially to total burden of cancer morbidity and mortality in the United States. Family history is a known risk factor for EC, thus genetic factors may play a role in EC pathogenesis. Three previous genome-wide association studies (GWAS) have found only one locus associated with EC, suggesting that common variants with large effects may not contribute greatly to EC risk. Alternatively, we hypothesize that rare variants may contribute to EC risk. We conducted an exome-wide association study (EXWAS) of EC using the Infinium HumanExome BeadChip in order to identify rare variants associated with EC risk. We successfully genotyped 177,139 variants in a multiethnic population of 1,055 cases and 1,778 controls from four studies that were part of the Epidemiology of Endometrial Cancer Consortium (E2C2). No variants reached global significance in the study, suggesting that more power is needed to detect modest associations between rare genetic variants and risk of EC.
doi:10.1371/journal.pone.0097045
PMCID: PMC4014590  PMID: 24810602
23.  Body Mass Index and Physical Activity at Different Ages and Risk of Multiple Myeloma in the NIH-AARP Diet and Health Study 
American Journal of Epidemiology  2013;177(8):776-786.
Several studies have reported an increased risk of multiple myeloma associated with excess body weight. We investigated the risk of multiple myeloma in relation to separate measures of adiposity and energy balance at different ages in the National Institutes of Health-AARP Diet and Health Study, a large prospective cohort study in the United States. Participants completed a baseline questionnaire (1995–1996; n = 485,049), and a subset of participants completed a second questionnaire (1996–1997; n = 305,618) in which we solicited more detailed exposure information. Hazard ratios and 95% confidence intervals were estimated for the risk of multiple myeloma (overall, n = 813; subset, n = 489) in relation to several measures of obesity and leisure time physical activity. Multiple myeloma risk was associated with increasing body mass index (BMI) at cohort entry (per 5-kg/m2 increase, hazard ratio (HR) = 1.10, 95% confidence interval (CI): 1.00, 1.22); similar associations were observed for BMI at age 50 years (HR = 1.14, 95% CI: 1.02, 1.28), age 35 years (HR = 1.20, 95% CI: 1.05, 1.36), and age 18 years (HR = 1.13, 95% CI: 0.98, 1.32) without adjustment for baseline BMI. Risk of multiple myeloma was not associated with physical activity level at any age. These findings support the hypothesis that excess body weight, both in early adulthood and later in life, is a risk factor for multiple myeloma and suggest that maintaining a healthy body weight throughout life may reduce multiple myeloma risk.
doi:10.1093/aje/kws295
PMCID: PMC3668425  PMID: 23543160
body mass index; multiple myeloma; obesity; overweight; physical activity
24.  Transforming Epidemiology for 21st Century Medicine and Public Health 
In 2012, the National Cancer Institute (NCI) engaged the scientific community to provide a vision for cancer epidemiology in the 21st century. Eight overarching thematic recommendations, with proposed corresponding actions for consideration by funding agencies, professional societies, and the research community emerged from the collective intellectual discourse. The themes are (i) extending the reach of epidemiology beyond discovery and etiologic research to include multilevel analysis, intervention evaluation, implementation, and outcomes research; (ii) transforming the practice of epidemiology by moving towards more access and sharing of protocols, data, metadata, and specimens to foster collaboration, to ensure reproducibility and replication, and accelerate translation; (iii) expanding cohort studies to collect exposure, clinical and other information across the life course and examining multiple health-related endpoints; (iv) developing and validating reliable methods and technologies to quantify exposures and outcomes on a massive scale, and to assess concomitantly the role of multiple factors in complex diseases; (v) integrating “big data” science into the practice of epidemiology; (vi) expanding knowledge integration to drive research, policy and practice; (vii) transforming training of 21st century epidemiologists to address interdisciplinary and translational research; and (viii) optimizing the use of resources and infrastructure for epidemiologic studies. These recommendations can transform cancer epidemiology and the field of epidemiology in general, by enhancing transparency, interdisciplinary collaboration, and strategic applications of new technologies. They should lay a strong scientific foundation for accelerated translation of scientific discoveries into individual and population health benefits.
doi:10.1158/1055-9965.EPI-13-0146
PMCID: PMC3625652  PMID: 23462917
big data; clinical trials; cohort studies; epidemiology; genomics; medicine; public health; technologies; training; translational research
25.  An Aggregated Analysis of Hormonal Factors and Endometrial Cancer Risk by Parity 
Cancer  2012;119(7):1393-1401.
Background
Nulliparity is associated with an increased risk of endometrial cancer. Less clear is whether nulliparity modifies the association between other established hormone-related risk factors. The proportion of nulliparous women has increased since the mid-1970s, but most individual studies are too small to test the hypothesis that endometrial cancer risk factors may be more strongly associated with risk among nulliparous women compared with parous women.
Methods
We aggregated data on 26,936 postmenopausal, Caucasian nulliparous women (360 endometrial cancers) and 146,583 postmenopausal Caucasian parous women (1,378 endometrial cancers) from four U.S. prospective studies (1979–2006). We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) in stratified analyses.
Results
As expected, endometrial cancer risk was higher among nulliparous women than among parous women (HR, nulliparous vs. parous = 1.42, 95% CI 1.26 to 1.60). Stratified associations between endometrial cancer and hormone-related risk factors did not differ among nulliparous vs. parous women: among both groups, oral contraceptives and earlier menopause were associated with reduced risk. The highest HRs were for obesity; body mass index ≥30 kg/m2 (vs. <25 kg/m2) increased endometrial cancer risk three-fold among nulliparous (HR= 3.04, 95% CI 2.34 to 3.94) and parous (HR= 2.88, 95% CI 2.52 to 3.29) women.
Conclusions
The results from this large, pooled analysis of data from four large prospective studies suggest that nulliparity does not modify endometrial cancer risks associated with established hormone-related risk factors.
doi:10.1002/cncr.27909
PMCID: PMC3744666  PMID: 23280123
endometrial cancer; nulliparity; reproductive history; oral contraceptives; hormonal; obesity

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