Publications by authors named "Michael Thun"

313 Publications

Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry.

Am J Hum Genet 2021 04 12;108(4):564-582. Epub 2021 Mar 12.

The Charles R. Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.
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http://dx.doi.org/10.1016/j.ajhg.2021.02.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059339PMC
April 2021

Higher Lung Cancer Incidence in Young Women Than Young Men in the United States.

N Engl J Med 2018 May;378(21):1999-2009

From Surveillance and Health Services Research, American Cancer Society, Atlanta (A.J., K.D.M., J.M., R.L.S., S.A.F., F.I., M.J.T.); and the Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD (S.S.D.).

Background: Previous studies showed a higher incidence of lung cancer among young women than among young men in the United States. Whether this pattern has continued in contemporary birth cohorts and, if so, whether it can be fully explained by sex differences in smoking behaviors are unknown.

Methods: We examined the nationwide population-based incidence of lung cancer according to sex, race or ethnic group, age group (30 to 34, 35 to 39, 40 to 44, 45 to 49, and 50 to 54 years), year of birth (1945 to 1980), and calendar period of diagnosis (1995-1999, 2000-2004, 2005-2009, and 2010-2014), and we calculated female-to-male incidence rate ratios. We also examined the prevalence of cigarette smoking, using data from the National Health Interview Survey from 1970 to 2016.

Results: Over the past two decades, the age-specific incidence of lung cancer has generally decreased among both men and women 30 to 54 years of age in all races and ethnic groups, but the declines among men have been steeper. Consequently, among non-Hispanic whites, the female-to-male incidence rate ratios increased, exceeding 1.0 in the age groups of 30 to 34, 35 to 39, 40 to 44, and 45 to 49 years. For example, the female-to-male incidence rate ratio among whites 40 to 44 years of age increased from 0.88 (95% confidence interval [CI], 0.84 to 0.92) during the 1995-1999 period to 1.17 (95% CI, 1.11 to 1.23) during the 2010-2014 period. The crossover in sex-specific rates occurred among non-Hispanic whites born since 1965. Sex-specific incidence rates converged among non-Hispanic blacks, Hispanics, and non-Hispanic Asians and Pacific Islanders but crossed over from a higher incidence among men to a higher incidence among women only among Hispanics. The prevalence of cigarette smoking among women born since 1965 has approached, but generally not exceeded, the prevalence among men.

Conclusions: The patterns of historically higher incidence rates of lung cancer among men than among women have reversed among non-Hispanic whites and Hispanics born since the mid-1960s, and they are not fully explained by sex differences in smoking behaviors. Future studies are needed to identify reasons for the higher incidence of lung cancer among young women. (Funded by the American Cancer Society.).
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http://dx.doi.org/10.1056/NEJMoa1715907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717174PMC
May 2018

Pooled analysis of active cigarette smoking and invasive breast cancer risk in 14 cohort studies.

Int J Epidemiol 2017 06;46(3):881-893

Epidemiology Research Program, American Cancer Society, Atlanta, GA, USA.

Background: The 2014 US Surgeon General's report noted research gaps necessary to determine a causal relationship between active cigarette smoking and invasive breast cancer risk, including the role of alcohol consumption, timing of exposure, modification by menopausal status and heterogeneity by oestrogen receptor (ER) status.

Methods: To address these issues, we pooled data from 14 cohort studies contributing 934 681 participants (36 060 invasive breast cancer cases). Cox proportional hazard regression models were used to calculate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs).

Results: Smoking duration before first birth was positively associated with risk ( P -value for trend = 2 × 10 -7 ) with the highest HR for initiation >10 years before first birth (HR = 1.18, CI 1.12-1.24). Effect modification by current alcohol consumption was evident for the association with smoking duration before first birth ( P -value=2×10 -4 ); compared with never-smoking non-drinkers, initiation >10 years before first birth was associated with risk in every category of alcohol intake, including non-drinkers (HR = 1.15, CI 1.04-1.28) and those who consumed at least three drinks per day (1.85, 1.55-2.21). Associations with smoking before first birth were limited to risk of ER+ breast cancer ( P -value for homogeneity=3×10 -3 ). Other smoking timing and duration characteristics were associated with risk even after controlling for alcohol, but were not associated with risk in non-drinkers. Effect modification by menopause was not evident.

Conclusions: Smoking, particularly if initiated before first birth, was modestly associated with ER+ breast cancer risk that was not confounded by amount of adult alcohol intake. Possible links with breast cancer provide additional motivation for young women to not initiate smoking.
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http://dx.doi.org/10.1093/ije/dyw288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837778PMC
June 2017

Body-mass index and all-cause mortality: individual-participant-data meta-analysis of 239 prospective studies in four continents.

Lancet 2016 08 13;388(10046):776-86. Epub 2016 Jul 13.

Background: Overweight and obesity are increasing worldwide. To help assess their relevance to mortality in different populations we conducted individual-participant data meta-analyses of prospective studies of body-mass index (BMI), limiting confounding and reverse causality by restricting analyses to never-smokers and excluding pre-existing disease and the first 5 years of follow-up.

Methods: Of 10 625 411 participants in Asia, Australia and New Zealand, Europe, and North America from 239 prospective studies (median follow-up 13·7 years, IQR 11·4-14·7), 3 951 455 people in 189 studies were never-smokers without chronic diseases at recruitment who survived 5 years, of whom 385 879 died. The primary analyses are of these deaths, and study, age, and sex adjusted hazard ratios (HRs), relative to BMI 22·5-<25·0 kg/m(2).

Findings: All-cause mortality was minimal at 20·0-25·0 kg/m(2) (HR 1·00, 95% CI 0·98-1·02 for BMI 20·0-<22·5 kg/m(2); 1·00, 0·99-1·01 for BMI 22·5-<25·0 kg/m(2)), and increased significantly both just below this range (1·13, 1·09-1·17 for BMI 18·5-<20·0 kg/m(2); 1·51, 1·43-1·59 for BMI 15·0-<18·5) and throughout the overweight range (1·07, 1·07-1·08 for BMI 25·0-<27·5 kg/m(2); 1·20, 1·18-1·22 for BMI 27·5-<30·0 kg/m(2)). The HR for obesity grade 1 (BMI 30·0-<35·0 kg/m(2)) was 1·45, 95% CI 1·41-1·48; the HR for obesity grade 2 (35·0-<40·0 kg/m(2)) was 1·94, 1·87-2·01; and the HR for obesity grade 3 (40·0-<60·0 kg/m(2)) was 2·76, 2·60-2·92. For BMI over 25·0 kg/m(2), mortality increased approximately log-linearly with BMI; the HR per 5 kg/m(2) units higher BMI was 1·39 (1·34-1·43) in Europe, 1·29 (1·26-1·32) in North America, 1·39 (1·34-1·44) in east Asia, and 1·31 (1·27-1·35) in Australia and New Zealand. This HR per 5 kg/m(2) units higher BMI (for BMI over 25 kg/m(2)) was greater in younger than older people (1·52, 95% CI 1·47-1·56, for BMI measured at 35-49 years vs 1·21, 1·17-1·25, for BMI measured at 70-89 years; pheterogeneity<0·0001), greater in men than women (1·51, 1·46-1·56, vs 1·30, 1·26-1·33; pheterogeneity<0·0001), but similar in studies with self-reported and measured BMI.

Interpretation: The associations of both overweight and obesity with higher all-cause mortality were broadly consistent in four continents. This finding supports strategies to combat the entire spectrum of excess adiposity in many populations.

Funding: UK Medical Research Council, British Heart Foundation, National Institute for Health Research, US National Institutes of Health.
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http://dx.doi.org/10.1016/S0140-6736(16)30175-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4995441PMC
August 2016

Smoking and mortality--beyond established causes.

N Engl J Med 2015 Feb;372(7):631-40

From the Epidemiology Research Program, American Cancer Society, Atlanta (B.D.C., M.J.T., E.J.J.); the Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD (C.C.A., N.D.F., P.H.); the Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston (D.F., F.E.S.); the Department of Medicine, Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham (C.E.L.); the Department of Medicine, Division of Preventive and Behavioral Medicine, University of Massachusetts Medical School, Worcester (J.K.O.); and the Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle (R.L.P.).

Background: Mortality among current smokers is 2 to 3 times as high as that among persons who never smoked. Most of this excess mortality is believed to be explained by 21 common diseases that have been formally established as caused by cigarette smoking and are included in official estimates of smoking-attributable mortality in the United States. However, if smoking causes additional diseases, these official estimates may significantly underestimate the number of deaths attributable to smoking.

Methods: We pooled data from five contemporary U.S. cohort studies including 421,378 men and 532,651 women 55 years of age or older. Participants were followed from 2000 through 2011, and relative risks and 95% confidence intervals were estimated with the use of Cox proportional-hazards models adjusted for age, race, educational level, daily alcohol consumption, and cohort.

Results: During the follow-up period, there were 181,377 deaths, including 16,475 among current smokers. Overall, approximately 17% of the excess mortality among current smokers was due to associations with causes that are not currently established as attributable to smoking. These included associations between current smoking and deaths from renal failure (relative risk, 2.0; 95% confidence interval [CI], 1.7 to 2.3), intestinal ischemia (relative risk, 6.0; 95% CI, 4.5 to 8.1), hypertensive heart disease (relative risk, 2.4; 95% CI, 1.9 to 3.0), infections (relative risk, 2.3; 95% CI, 2.0 to 2.7), various respiratory diseases (relative risk, 2.0; 95% CI, 1.6 to 2.4), breast cancer (relative risk, 1.3; 95% CI, 1.2 to 1.5), and prostate cancer (relative risk, 1.4; 95% CI, 1.2 to 1.7). Among former smokers, the relative risk for each of these outcomes declined as the number of years since quitting increased.

Conclusions: A substantial portion of the excess mortality among current smokers between 2000 and 2011 was due to associations with diseases that have not been formally established as caused by smoking. These associations should be investigated further and, when appropriate, taken into account when the mortality burden of smoking is investigated. (Funded by the American Cancer Society.).
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http://dx.doi.org/10.1056/NEJMsa1407211DOI Listing
February 2015

Additive interactions between susceptibility single-nucleotide polymorphisms identified in genome-wide association studies and breast cancer risk factors in the Breast and Prostate Cancer Cohort Consortium.

Am J Epidemiol 2014 Nov 25;180(10):1018-27. Epub 2014 Sep 25.

Additive interactions can have public health and etiological implications but are infrequently reported. We assessed departures from additivity on the absolute risk scale between 9 established breast cancer risk factors and 23 susceptibility single-nucleotide polymorphisms (SNPs) identified from genome-wide association studies among 10,146 non-Hispanic white breast cancer cases and 12,760 controls within the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium. We estimated the relative excess risk due to interaction and its 95% confidence interval for each pairwise combination of SNPs and nongenetic risk factors using age- and cohort-adjusted logistic regression models. After correction for multiple comparisons, we identified a statistically significant relative excess risk due to interaction (uncorrected P = 4.51 × 10(-5)) between a SNP in the DNA repair protein RAD51 homolog 2 gene (RAD51L1; rs10483813) and body mass index (weight (kg)/height (m)(2)). We also compared additive and multiplicative polygenic risk prediction models using per-allele odds ratio estimates from previous studies for breast-cancer susceptibility SNPs and observed that the multiplicative model had a substantially better goodness of fit than the additive model.
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http://dx.doi.org/10.1093/aje/kwu214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4224360PMC
November 2014

Pleiotropic associations of risk variants identified for other cancers with lung cancer risk: the PAGE and TRICL consortia.

J Natl Cancer Inst 2014 Apr 28;106(4):dju061. Epub 2014 Mar 28.

Affiliations of authors: Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA (SLP, FRS, CAH); Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA (MDF, JMK, AY, YL, UP, CC, CK); Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, University of Edinburgh and Medical Research Council Human Genetics Unit, Edinburgh, UK (MT); Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI (CPC, LRW, LL); Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Hanover, NH (YH, CIA); Department of Epidemiology (S-AL, AB, KEN, GH) and Carolina Center for Genome Sciences (KEN), University of North Carolina, Chapel Hill, NC; Molecular Physiology and Biophysics (LD, DCC), Center for Human Genetics Research (LD, RG, HD, DCC, WSB), Vanderbilt Epidemiology Center (JHF), and Biomedical Informatics (WSB), Vanderbilt University, Nashville, TN; Division of Genomic Medicine, National Human Genome Research Institute (LH), and Division of Cancer Epidemiology and Genetics, National Cancer Institute (DA, NC, MTL), National Institutes of Health, Bethesda, MD; Department of Statistics and Biostatistics, Rutgers University, Piscataway, NJ (SB); Information Sciences Institute, University of Southern California, Marina del Rey, CA (ED); Department of Oncology, School of Medicine, Wayne State University, Detroit, Michigan (MLC); M.D. Anderson Cancer Center, Houston, TX (WC, MP); Harvard University School of Public Health, Boston, MA (DCC); Roy Castle Lung Cancer Research Programme, Department of Molecular and Clinical Cancer Medicine, The University of Liverpool Cancer Research Centre, Institute of Translational Medicine, The University of Liverpool, Liverpool, UK (JKF); Department of Genetic Epidemiology, University Medical Centre Göttingen, Göttingen, Germany (HB); DKFZ-German Cancer Research Center and Translatio

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.
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http://dx.doi.org/10.1093/jnci/dju061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3982896PMC
April 2014

Body mass index and risk of death in Asian Americans.

Am J Public Health 2014 Mar 16;104(3):520-5. Epub 2014 Jan 16.

Yikyung Park, Cari M. Kitahara, Steven C. Moore, Amy Berrington de Gonzalez, D. Michal Freedman, Robert N. Hoover, Martha S. Linet, Mark Purdue, Catherine Schairer, and Patricia Hartge are with the Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD. Sophia Wang and Leslie Bernstein are with the Division of Cancer Etiology, Department of Population Sciences, Beckman Research Institute and the City of Hope, Duarte, CA. Ellen T. Chang is with Health Sciences Practice, Exponent Inc, Menlo Park, CA. Alan J. Flint and Walter C. Willett are with the Department of Nutrition, Harvard School of Public Health, Boston, MA. J. Michael Gaziano, Howard D. Sesso, and Walter C. Willett are with the Division of Preventive Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, MA. Kim Robien is with Departments of Epidemiology and Biostatistics and Exercise Science, School of Public Health and Health Services, George Washington University, Washington, DC. Emily White is with the Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Department of Epidemiology, University of Washington, Seattle. Bradley J. Willcox is with the Pacific Health Research and Education Institute and Queen's Medical Center, Honolulu, HI. Michael J. Thun is with the Department of Epidemiology, Epidemiology and Surveillance Research, American Cancer Society, Atlanta, GA.

Objectives: We investigated the association between body mass index (BMI) and mortality among Asian Americans.

Methods: We pooled data from prospective cohort studies with 20 672 Asian American adults with no baseline cancer or heart disease history. We estimated hazard ratios and 95% confidence intervals (CIs) with Cox proportional hazards models.

Results: A high, but not low, BMI was associated with increased risk of total mortality among individuals aged 35 to 69 years. The BMI was not related to total mortality among individuals aged 70 years and older. With a BMI 22.5 to < 25 as the reference category among never-smokers aged 35 to 69 years, the hazard ratios for total mortality were 0.83 (95% CI = 0.47, 1.47) for BMI 15 to < 18.5; 0.91 (95% CI = 0.62, 1.32) for BMI 18.5 to < 20; 1.08 (95% CI = 0.86, 1.36) for BMI 20 to < 22.5; 1.14 (95% CI = 0.90, 1.44) for BMI 25 to < 27.5; 1.13 (95% CI = 0.79, 1.62) for BMI 27.5 to < 30; 1.82 (95% CI = 1.25, 2.64) for BMI 30 to < 35; and 2.09 (95% CI = 1.06, 4.11) for BMI 35 to 50. Higher BMI was also related to increased cardiovascular disease and cancer mortality.

Conclusions: High BMI is associated with increased mortality risk among Asian Americans.
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http://dx.doi.org/10.2105/AJPH.2013.301573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3953786PMC
March 2014

Spatial analysis of air pollution and mortality in California.

Am J Respir Crit Care Med 2013 Sep;188(5):593-9

Division of Environmental Health Sciences, School of Public Health, University of California Berkeley, USA.

Rationale: Although substantial scientific evidence suggests that chronic exposure to ambient air pollution contributes to premature mortality, uncertainties exist in the size and consistency of this association. Uncertainty may arise from inaccurate exposure assessment.

Objectives: To assess the associations of three types of air pollutants (fine particulate matter, ozone [O3], and nitrogen dioxide [NO2]) with the risk of mortality in a large cohort of California adults using individualized exposure assessments.

Methods: For fine particulate matter and NO2, we used land use regression models to derive predicted individualized exposure at the home address. For O3, we estimated exposure with an inverse distance weighting interpolation. Standard and multilevel Cox survival models were used to assess the association between air pollution and mortality.

Measurements And Main Results: Data for 73,711 subjects who resided in California were abstracted from the American Cancer Society Cancer Prevention II Study cohort, with baseline ascertainment of individual characteristics in 1982 and follow-up of vital status through to 2000. Exposure data were derived from government monitors. Exposure to fine particulate matter, O3, and NO2 was positively associated with ischemic heart disease mortality. NO2 (a marker for traffic pollution) and fine particulate matter were also associated with mortality from all causes combined. Only NO2 had significant positive association with lung cancer mortality.

Conclusions: Using the first individualized exposure assignments in this important cohort, we found positive associations of fine particulate matter, O3, and NO2 with mortality. The positive associations of NO2 suggest that traffic pollution relates to premature death.
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http://dx.doi.org/10.1164/rccm.201303-0609OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5447295PMC
September 2013

A meta-analysis identifies new loci associated with body mass index in individuals of African ancestry.

Nat Genet 2013 Jun 14;45(6):690-6. Epub 2013 Apr 14.

The Center for Observational Research, Amgen, Inc. Thousand Oaks, California, USA.

Genome-wide association studies (GWAS) have identified 36 loci associated with body mass index (BMI), predominantly in populations of European ancestry. We conducted a meta-analysis to examine the association of >3.2 million SNPs with BMI in 39,144 men and women of African ancestry and followed up the most significant associations in an additional 32,268 individuals of African ancestry. We identified one new locus at 5q33 (GALNT10, rs7708584, P = 3.4 × 10(-11)) and another at 7p15 when we included data from the GIANT consortium (MIR148A-NFE2L3, rs10261878, P = 1.2 × 10(-10)). We also found suggestive evidence of an association at a third locus at 6q16 in the African-ancestry sample (KLHL32, rs974417, P = 6.9 × 10(-8)). Thirty-two of the 36 previously established BMI variants showed directionally consistent effect estimates in our GWAS (binomial P = 9.7 × 10(-7)), five of which reached genome-wide significance. These findings provide strong support for shared BMI loci across populations, as well as for the utility of studying ancestrally diverse populations.
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http://dx.doi.org/10.1038/ng.2608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3694490PMC
June 2013

Common genetic polymorphisms modify the effect of smoking on absolute risk of bladder cancer.

Cancer Res 2013 Apr 27;73(7):2211-20. Epub 2013 Mar 27.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.

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 assess 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 U.S. males aged 50 years. Six 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 U.S. 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 with 2,000 cases prevented by a similar effort in the lowest PRS quartile (P(additive) = 1 × 10(-4)). Thus, the potential impact of eliminating smoking on the 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.
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http://dx.doi.org/10.1158/0008-5472.CAN-12-2388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3688270PMC
April 2013

Active smoking and breast cancer risk: original cohort data and meta-analysis.

J Natl Cancer Inst 2013 Apr 28;105(8):515-25. Epub 2013 Feb 28.

Epidemiology Research Program, American Cancer Society, Atlanta, GA 30303, USA.

Background: The relationship between active cigarette smoking and breast cancer risk remains controversial because of unresolved issues of confounding and dose response.

Methods: To investigate these issues further, we analyzed data from 73 388 women in the American Cancer Society's Cancer Prevention Study II (CPS-II) Nutrition Cohort. Analyses were based on 3721 invasive breast cancer case patients identified during a median follow-up of 13.8 years. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated from multivariable-adjusted Cox proportional hazard regression models. P values were two-sided. We also conducted meta-analyses of our results with those published from 14 other cohort studies.

Results: In CPS-II, incidence was higher in current (HR = 1.24, 95% CI = 1.07 to 1.42) and former smokers (HR =1.13, 95% CI = 1.06 to 1.21) than in never smokers. Women who initiated smoking before menarche (HR = 1.61, 95% CI = 1.10 to 2.34) or after menarche but 11 or more years before first birth (HR = 1.45, 95% CI = 1.21 to 1.74) had higher risk (P trend = .03). No relationships were observed with other smoking parameters. Alcohol consumption did not confound associations with smoking status, although neither current nor former smoking were associated with risk among never drinkers (P interaction = .11). In meta-analyses, current (HR = 1.12, 95% CI = 1.08 to 1.16) and former smoking (HR = 1.09, 95% CI = 1.04 to 1.15) were weakly associated with risk; a stronger association (HR = 1.21, 95% CI = 1.14 to 1.28) was observed in women who initiated smoking before first birth.

Conclusions: These results support the hypothesis that active smoking is associated with increased breast cancer risk for women who initiate smoking before first birth and suggest that smoking might play a role in breast cancer initiation.
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http://dx.doi.org/10.1093/jnci/djt023DOI Listing
April 2013

50-year trends in smoking-related mortality in the United States.

N Engl J Med 2013 Jan;368(4):351-64

Department of Epidemiology, American Cancer Society, Atlanta, GA 30303-1002, USA.

Background: The disease risks from cigarette smoking increased in the United States over most of the 20th century, first among male smokers and later among female smokers. Whether these risks have continued to increase during the past 20 years is unclear.

Methods: We measured temporal trends in mortality across three time periods (1959-1965, 1982-1988, and 2000-2010), comparing absolute and relative risks according to sex and self-reported smoking status in two historical cohort studies and in five pooled contemporary cohort studies, among participants who became 55 years of age or older during follow-up.

Results: For women who were current smokers, as compared with women who had never smoked, the relative risks of death from lung cancer were 2.73, 12.65, and 25.66 in the 1960s, 1980s, and contemporary cohorts, respectively; corresponding relative risks for male current smokers, as compared with men who had never smoked, were 12.22, 23.81, and 24.97. In the contemporary cohorts, male and female current smokers also had similar relative risks for death from chronic obstructive pulmonary disease (COPD) (25.61 for men and 22.35 for women), ischemic heart disease (2.50 for men and 2.86 for women), any type of stroke (1.92 for men and 2.10 for women), and all causes combined (2.80 for men and 2.76 for women). Mortality from COPD among male smokers continued to increase in the contemporary cohorts in nearly all the age groups represented in the study and within each stratum of duration and intensity of smoking. Among men 55 to 74 years of age and women 60 to 74 years of age, all-cause mortality was at least three times as high among current smokers as among those who had never smoked. Smoking cessation at any age dramatically reduced death rates.

Conclusions: The risk of death from cigarette smoking continues to increase among women and the increased risks are now nearly identical for men and women, as compared with persons who have never smoked. Among men, the risks associated with smoking have plateaued at the high levels seen in the 1980s, except for a continuing, unexplained increase in mortality from COPD.
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http://dx.doi.org/10.1056/NEJMsa1211127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3632080PMC
January 2013

21st-century hazards of smoking and benefits of cessation in the United States.

N Engl J Med 2013 Jan;368(4):341-50

Center for Global Health Research, Toronto, ON M5C 1N8, Canada.

Background: Extrapolation from studies in the 1980s suggests that smoking causes 25% of deaths among women and men 35 to 69 years of age in the United States. Nationally representative measurements of the current risks of smoking and the benefits of cessation at various ages are unavailable.

Methods: We obtained smoking and smoking-cessation histories from 113,752 women and 88,496 men 25 years of age or older who were interviewed between 1997 and 2004 in the U.S. National Health Interview Survey and related these data to the causes of deaths that occurred by December 31, 2006 (8236 deaths in women and 7479 in men). Hazard ratios for death among current smokers, as compared with those who had never smoked, were adjusted for age, educational level, adiposity, and alcohol consumption.

Results: For participants who were 25 to 79 years of age, the rate of death from any cause among current smokers was about three times that among those who had never smoked (hazard ratio for women, 3.0; 99% confidence interval [CI], 2.7 to 3.3; hazard ratio for men, 2.8; 99% CI, 2.4 to 3.1). Most of the excess mortality among smokers was due to neoplastic, vascular, respiratory, and other diseases that can be caused by smoking. The probability of surviving from 25 to 79 years of age was about twice as great in those who had never smoked as in current smokers (70% vs. 38% among women and 61% vs. 26% among men). Life expectancy was shortened by more than 10 years among the current smokers, as compared with those who had never smoked. Adults who had quit smoking at 25 to 34, 35 to 44, or 45 to 54 years of age gained about 10, 9, and 6 years of life, respectively, as compared with those who continued to smoke.

Conclusions: Smokers lose at least one decade of life expectancy, as compared with those who have never smoked. Cessation before the age of 40 years reduces the risk of death associated with continued smoking by about 90%.
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http://dx.doi.org/10.1056/NEJMsa1211128DOI Listing
January 2013

Aspirin and other nonsteroidal anti-inflammatory drugs and risk of non-hodgkin lymphoma.

Cancer Epidemiol Biomarkers Prev 2013 Mar 17;22(3):422-8. Epub 2013 Jan 17.

Corresponding Author: Lauren R. Teras, Epidemiology Research Program, American Cancer Society, 250 Williams Street NW, Atlanta, GA 30303, USA.

Few large prospective studies have examined associations between nonsteroidal anti-inflammatory drug (NSAID) use and non-Hodgkin lymphoma (NHL). We examined the association between NSAID use and NHL incidence among 149,570 participants in the Cancer Prevention Study-II Nutrition cohort. Aspirin and nonaspirin NSAID use were reported at enrollment in 1992 and updated on periodic follow-up questionnaires. During follow-up through 2007, 1,709 incident NHLs were identified. Time-dependent hazard ratios were calculated using extended Cox regression. Compared to no use, current use of 60+ NSAID pills/month (aspirin and nonaspirin NSAIDs combined) was associated with slightly higher NHL incidence (hazard ratio [HR] = 1.26, 95% confidence interval [CI], 1.04-1.53), but no association with frequency of use was observed when NSAID exposure was lagged by approximately 2 years (HR = 1.08, 95% CI, 0.88-1.32). Long duration regular use (current use of 30+ pills/month for ≥5 years) was not associated with NHL incidence (HR = 1.09, 95% CI, 0.91-1.33). In subtype analyses, current use of 60+ NSAID pills/month was associated with follicular lymphoma incidence (HR = 1.87, 95% CI, 1.08-3.24). This association persisted when NSAID exposure was lagged (HR = 1.76, 95% CI, 1.04-2.98) and was similar for aspirin and nonaspirin NSAIDs. The association of current, but not lagged, NSAID use with risk of all NHL could be attributable to use of NSAIDs to relieve symptoms of undiagnosed NHL. However, the association with follicular lymphoma persisted in analyses where NSAID use was lagged and should be investigated further. These findings are particularly important for aspirin as the risks and benefits of prophylactic daily use are weighed.
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http://dx.doi.org/10.1158/1055-9965.EPI-12-1158DOI Listing
March 2013

Leisure time physical activity of moderate to vigorous intensity and mortality: a large pooled cohort analysis.

PLoS Med 2012 6;9(11):e1001335. Epub 2012 Nov 6.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.

Background: Leisure time physical activity reduces the risk of premature mortality, but the years of life expectancy gained at different levels remains unclear. Our objective was to determine the years of life gained after age 40 associated with various levels of physical activity, both overall and according to body mass index (BMI) groups, in a large pooled analysis.

Methods And Findings: We examined the association of leisure time physical activity with mortality during follow-up in pooled data from six prospective cohort studies in the National Cancer Institute Cohort Consortium, comprising 654,827 individuals, 21-90 y of age. Physical activity was categorized by metabolic equivalent hours per week (MET-h/wk). Life expectancies and years of life gained/lost were calculated using direct adjusted survival curves (for participants 40+ years of age), with 95% confidence intervals (CIs) derived by bootstrap. The study includes a median 10 y of follow-up and 82,465 deaths. A physical activity level of 0.1-3.74 MET-h/wk, equivalent to brisk walking for up to 75 min/wk, was associated with a gain of 1.8 (95% CI: 1.6-2.0) y in life expectancy relative to no leisure time activity (0 MET-h/wk). Higher levels of physical activity were associated with greater gains in life expectancy, with a gain of 4.5 (95% CI: 4.3-4.7) y at the highest level (22.5+ MET-h/wk, equivalent to brisk walking for 450+ min/wk). Substantial gains were also observed in each BMI group. In joint analyses, being active (7.5+ MET-h/wk) and normal weight (BMI 18.5-24.9) was associated with a gain of 7.2 (95% CI: 6.5-7.9) y of life compared to being inactive (0 MET-h/wk) and obese (BMI 35.0+). A limitation was that physical activity and BMI were ascertained by self report.

Conclusions: More leisure time physical activity was associated with longer life expectancy across a range of activity levels and BMI groups. Please see later in the article for the Editors' Summary.
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http://dx.doi.org/10.1371/journal.pmed.1001335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3491006PMC
April 2013

Premorbid body mass index and risk of amyotrophic lateral sclerosis.

Amyotroph Lateral Scler Frontotemporal Degener 2013 Apr 29;14(3):205-11. Epub 2012 Oct 29.

Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA.

Our objective was to determine if amyotrophic lateral sclerosis (ALS) risk varies according to body mass index (BMI) captured up to three decades earlier. At baseline 537,968 females and 562,942 males in five ongoing cohorts reported height, current weight and weight at age 18/21 years. During 14-28 years of follow-up, 1153 participants developed ALS. Cohort-specific Cox proportional hazards models were used to estimate rates that were then pooled with random-effects models. Results showed that lower BMI at baseline was associated with ALS; for each 5-unit increase in BMI, ALS rates were 21% lower (95% CI 14% 27%). Compared to individuals with healthy BMI, ALS rates were significantly lower among the overweight (RR = 0.76 (95% CI 0.62-0.93)) and obese (RR = 0.73 (95% CI 0.55-0.96)). Among never smokers the association persisted: RR = 0.75 (95% CI 0.65-0.85) for each 5-unit increase. Excluding the first seven years of follow-up, the associations were materially unchanged suggesting that weight loss from undiagnosed disease does not fully explain the findings. Overall, 75% of males and females had a healthy BMI at age 18/21 years, 15% of males and 8% of females were overweight or obese; there was no association with ALS although numbers with an unhealthy weight were small. In conclusion, these findings support an association between lower premorbid BMI and ALS.
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http://dx.doi.org/10.3109/21678421.2012.735240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3615420PMC
April 2013

A meta-analysis of genome-wide association studies to identify prostate cancer susceptibility loci associated with aggressive and non-aggressive disease.

Hum Mol Genet 2013 Jan 12;22(2):408-15. Epub 2012 Oct 12.

Strangeways Laboratory, Centre for Cancer Genetic Epidemiology, Worts Causeway, Cambridge CB1 8RN, UK.

Genome-wide association studies (GWAS) have identified multiple common genetic variants associated with an increased risk of prostate cancer (PrCa), but these explain less than one-third of the heritability. To identify further susceptibility alleles, we conducted a meta-analysis of four GWAS including 5953 cases of aggressive PrCa and 11 463 controls (men without PrCa). We computed association tests for approximately 2.6 million SNPs and followed up the most significant SNPs by genotyping 49 121 samples in 29 studies through the international PRACTICAL and BPC3 consortia. We not only confirmed the association of a PrCa susceptibility locus, rs11672691 on chromosome 19, but also showed an association with aggressive PrCa [odds ratio = 1.12 (95% confidence interval 1.03-1.21), P = 1.4 × 10(-8)]. This report describes a genetic variant which is associated with aggressive PrCa, which is a type of PrCa associated with a poorer prognosis.
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http://dx.doi.org/10.1093/hmg/dds425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3526158PMC
January 2013

Radon and nonrespiratory mortality in the American Cancer Society cohort.

Am J Epidemiol 2012 Nov 7;176(9):808-14. Epub 2012 Oct 7.

Faculty of Graduate and Postdoctoral Studies, University of Ottawa, Ontario, Canada.

Radon is a known cause of human lung cancer. Previously, the authors observed a significant positive association between mean county-level residential radon concentrations and lung cancer mortality in the Cancer Prevention Study II (CPS-II), a large prospective study of nearly 1.2 million participants recruited in 1982 by the American Cancer Society. There was also a significant positive association with mortality from chronic obstructive pulmonary disease. Because it is unclear whether radon is associated with mortality from other malignant or nonmalignant disease, the authors examined the association between radon and nonrespiratory mortality in the CPS-II. Mean county-level residential radon concentrations (mean = 53.5 (standard deviation: 38.0) Bq/m(3)) were linked to participants by their zip code at enrollment. Cox proportional hazards regression models were used to estimate adjusted hazard ratios and 95% confidence intervals for all-cause (excluding lung cancer and respiratory mortality) and cause-specific mortality associated with radon concentrations. A total of 811,961 participants in 2,754 counties were analyzed, including 265,477 deaths through 2006. There were no clear associations between radon and nonrespiratory mortality in the CPS-II. These findings suggest that residential radon is not associated with any other mortality beyond lung cancer or chronic obstructive pulmonary disease.
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http://dx.doi.org/10.1093/aje/kws198DOI Listing
November 2012

A meta-analysis of genome-wide association studies of breast cancer identifies two novel susceptibility loci at 6q14 and 20q11.

Hum Mol Genet 2012 Dec 13;21(24):5373-84. Epub 2012 Sep 13.

Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.

Genome-wide association studies (GWAS) of breast cancer defined by hormone receptor status have revealed loci contributing to susceptibility of estrogen receptor (ER)-negative subtypes. To identify additional genetic variants for ER-negative breast cancer, we conducted the largest meta-analysis of ER-negative disease to date, comprising 4754 ER-negative cases and 31 663 controls from three GWAS: NCI Breast and Prostate Cancer Cohort Consortium (BPC3) (2188 ER-negative cases; 25 519 controls of European ancestry), Triple Negative Breast Cancer Consortium (TNBCC) (1562 triple negative cases; 3399 controls of European ancestry) and African American Breast Cancer Consortium (AABC) (1004 ER-negative cases; 2745 controls). We performed in silico replication of 86 SNPs at P ≤ 1 × 10(-5) in an additional 11 209 breast cancer cases (946 with ER-negative disease) and 16 057 controls of Japanese, Latino and European ancestry. We identified two novel loci for breast cancer at 20q11 and 6q14. SNP rs2284378 at 20q11 was associated with ER-negative breast cancer (combined two-stage OR = 1.16; P = 1.1 × 10(-8)) but showed a weaker association with overall breast cancer (OR = 1.08, P = 1.3 × 10(-6)) based on 17 869 cases and 43 745 controls and no association with ER-positive disease (OR = 1.01, P = 0.67) based on 9965 cases and 22 902 controls. Similarly, rs17530068 at 6q14 was associated with breast cancer (OR = 1.12; P = 1.1 × 10(-9)), and with both ER-positive (OR = 1.09; P = 1.5 × 10(-5)) and ER-negative (OR = 1.16, P = 2.5 × 10(-7)) disease. We also confirmed three known loci associated with ER-negative (19p13) and both ER-negative and ER-positive breast cancer (6q25 and 12p11). Our results highlight the value of large-scale collaborative studies to identify novel breast cancer risk loci.
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http://dx.doi.org/10.1093/hmg/dds381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3510753PMC
December 2012

Prediction of breast cancer risk by genetic risk factors, overall and by hormone receptor status.

J Med Genet 2012 Sep;49(9):601-8

Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Objective: There is increasing interest in adding common genetic variants identified through genome wide association studies (GWAS) to breast cancer risk prediction models. First results from such models showed modest benefits in terms of risk discrimination. Heterogeneity of breast cancer as defined by hormone-receptor status has not been considered in this context. In this study we investigated the predictive capacity of 32 GWAS-detected common variants for breast cancer risk, alone and in combination with classical risk factors, and for tumours with different hormone receptor status.

Material And Methods: Within the Breast and Prostate Cancer Cohort Consortium, we analysed 6009 invasive breast cancer cases and 7827 matched controls of European ancestry, with data on classical breast cancer risk factors and 32 common gene variants identified through GWAS. Discriminatory ability with respect to breast cancer of specific hormone receptor-status was assessed with the age adjusted and cohort-adjusted concordance statistic (AUROC(a)). Absolute risk scores were calculated with external reference data. Integrated discrimination improvement was used to measure improvements in risk prediction.

Results: We found a small but steady increase in discriminatory ability with increasing numbers of genetic variants included in the model (difference in AUROC(a) going from 2.7% to 4%). Discriminatory ability for all models varied strongly by hormone receptor status.

Discussion And Conclusions: Adding information on common polymorphisms provides small but statistically significant improvements in the quality of breast cancer risk prediction models. We consistently observed better performance for receptor-positive cases, but the gain in discriminatory quality is not sufficient for clinical application.
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http://dx.doi.org/10.1136/jmedgenet-2011-100716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3793888PMC
September 2012

Chapter 3: Cohort life tables by smoking status, removing lung cancer as a cause of death.

Risk Anal 2012 Jul;32 Suppl 1:S25-38

University of Wisconsin–Madison, 975 University Ave., Madison, WI 53706, USA.

The purpose of this study was to develop life tables by smoking status removing lung cancer as a cause of death. These life tables are inputs to studies that compare the effectiveness of lung cancer treatments or interventions, and provide a way to quantify time until death from causes other than lung cancer. The study combined actuarial and statistical smoothing methods, as well as data from multiple sources, to develop separate life tables by smoking status, birth cohort, by single year of age, and by sex. For current smokers, separate life tables by smoking quintiles were developed based on the average number of cigarettes smoked per day by birth cohort. The end product is the creation of six non-lung-cancer life tables for males and six tables for females: five current smoker quintiles and one for never smokers. Tables for former smokers are linear combinations of the appropriate table based on the current smoker quintile before quitting smoking and the never smoker probabilities, plus added covariates for the smoking quit age and time since quitting.
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http://dx.doi.org/10.1111/j.1539-6924.2011.01662.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3594098PMC
July 2012

Influence of common genetic variation on lung cancer risk: meta-analysis of 14 900 cases and 29 485 controls.

Hum Mol Genet 2012 Nov 16;21(22):4980-95. Epub 2012 Aug 16.

International Agency for Research on Cancer, Lyon, France.

Recent genome-wide association studies (GWASs) have identified common genetic variants at 5p15.33, 6p21-6p22 and 15q25.1 associated with lung cancer risk. Several other genetic regions including variants of CHEK2 (22q12), TP53BP1 (15q15) and RAD52 (12p13) have been demonstrated to influence lung cancer risk in candidate- or pathway-based analyses. To identify novel risk variants for lung cancer, we performed a meta-analysis of 16 GWASs, totaling 14 900 cases and 29 485 controls of European descent. Our data provided increased support for previously identified risk loci at 5p15 (P = 7.2 × 10(-16)), 6p21 (P = 2.3 × 10(-14)) and 15q25 (P = 2.2 × 10(-63)). Furthermore, we demonstrated histology-specific effects for 5p15, 6p21 and 12p13 loci but not for the 15q25 region. Subgroup analysis also identified a novel disease locus for squamous cell carcinoma at 9p21 (CDKN2A/p16(INK4A)/p14(ARF)/CDKN2B/p15(INK4B)/ANRIL; rs1333040, P = 3.0 × 10(-7)) which was replicated in a series of 5415 Han Chinese (P = 0.03; combined analysis, P = 2.3 × 10(-8)). This large analysis provides additional evidence for the role of inherited genetic susceptibility to lung cancer and insight into biological differences in the development of the different histological types of lung cancer.
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http://dx.doi.org/10.1093/hmg/dds334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3607485PMC
November 2012

Daily aspirin use and cancer mortality in a large US cohort.

J Natl Cancer Inst 2012 Aug 10;104(16):1208-17. Epub 2012 Aug 10.

Epidemiology Research Program, American Cancer Society, Atlanta, GA 30303-1002, USA.

Background: A recent pooled analysis of randomized trials of daily aspirin for prevention of vascular events found a substantial reduction (relative risk [RR] = 0.63, 95% confidence interval [CI] = 0.49 to 0.82) in overall cancer mortality during follow-up occurring after 5 years on aspirin. However, the magnitude of the effect of daily aspirin use, particularly long-term use, on cancer mortality is uncertain.

Methods: We examined the association between daily aspirin use and overall cancer mortality among 100 139 men and women with no history of cancer in the Cancer Prevention Study II Nutrition Cohort. Cox proportional hazards regression models were used to estimate multivariable-adjusted relative risks (RRs) and 95% confidence intervals (CIs).

Results: Between 1997 and 2008, 5138 participants died from cancer. Compared with no use, daily aspirin use at baseline was associated with slightly lower cancer mortality, regardless of duration of daily use (for <5 years of use, RR = 0.92, 95% CI = 0.85 to 1.01; for ≥5 years of use, RR = 0.92, 95% CI = 0.83 to 1.02). Associations were slightly stronger in analyses that used updated aspirin information from periodic follow-up questionnaires and included 3373 cancer deaths (for <5 years of use, RR = 0.84, 95% CI = 0.76 to 0.94; for ≥5 years of use, RR = 0.84, 95% CI = 0.75 to 0.95).

Conclusion: These results are consistent with an association between recent daily aspirin use and modestly lower cancer mortality but suggest that any reduction in cancer mortality may be smaller than that observed with long-term aspirin use in the pooled trial analysis.
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http://dx.doi.org/10.1093/jnci/djs318DOI Listing
August 2012

Non-steroidal anti-inflammatory drugs and amyotrophic lateral sclerosis: results from five prospective cohort studies.

Amyotroph Lateral Scler 2012 Oct 7;13(6):573-9. Epub 2012 Aug 7.

Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts 02155, USA.

Animal and pathological studies suggest that inflammation may contribute to amyotrophic lateral sclerosis (ALS) pathology and that non-steroidal anti-inflammatory drugs (NSAIDs) might be protective. However, there are no prospective data on the relation between NSAID use and ALS risk in humans. The relation between NSAID use and ALS risk was explored in five large prospective cohort studies (the Nurses' Health Study, the Health Professionals Follow-up Study, the Cancer Prevention Study II Nutrition Cohort, the Multiethnic Cohort Study, and the National Institutes of Health - AARP Diet and Health Study). Detailed NSAID information was sought from 780,000 participants, 708 of whom developed ALS during follow-up. Cox proportional hazards models were used within each cohort and cohort-specific estimates were pooled with random effects models. Results showed that neither non-aspirin NSAID use, nor aspirin use was associated with ALS risk overall. The multivariable, pooled relative risk was 0.96 (95% CI 0.76-1.22) among non-aspirin NSAID users compared with non-users. Duration of NSAID use in years and frequency of NSAID use were not associated with ALS risk overall. In conclusion, the results do not support an overall effect of NSAIDs on ALS risk, but because NSAIDs have heterogeneous effects, a role of individual compounds cannot be excluded.
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http://dx.doi.org/10.3109/17482968.2012.703209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3474335PMC
October 2012

Learning from disease heterogeneity.

Lancet Oncol 2012 Sep 3;13(9):862-3. Epub 2012 Aug 3.

Epidemiology Research Program, American Cancer Society, Atlanta, GA 30316, USA.

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http://dx.doi.org/10.1016/S1470-2045(12)70365-0DOI Listing
September 2012

The association between cigarette smoking and non-Hodgkin lymphoid neoplasms in a large US cohort study.

Cancer Causes Control 2012 Aug 12;23(8):1231-40. Epub 2012 Jun 12.

Epidemiology Research Program, American Cancer Society, 250 Williams Street NW, Atlanta, GA 30033, USA.

Purpose: Results from studies of smoking and non-Hodgkin lymphoid neoplasms (NHL) are inconsistent. This study assessed whether this inconsistency might be due to the heterogeneous nature of the disease, to different relationships in subpopulations such as gender, or to chance.

Methods: We examined cigarette smoking status, initiation, intensity, and duration in relation to the risk of NHL, and subtypes of NHL in men and women from the American Cancer Society Cancer Prevention Study II Nutrition Cohort. From 1992 to 2007, 1,926 NHL cases were identified among 152,958 subjects. Extended Cox regression was used to compute multivariable rate ratios (RR) and 95 % confidence intervals (95 % CI).

Results: The RR (95 % CI) for current smoking associated with NHL incidence in women was 1.37 (1.04-1.81) and in men was 0.88 (0.65-1.19). Among current smokers, there was a positive relationship between years smoked and risk of NHL in women (p-trend < 0.01), but no association in men. In women, the positive associations with current smoking were strongest for follicular lymphoma (RR 2.13, 95 % CI 1.20-3.77) and chronic lymphocytic leukemia/small lymphocyte lymphoma (RR 1.75, 95 % CI 1.03-2.96). In men and women combined, current smoking was associated with an increased risk of T-cell lymphoma and a decreased risk of diffuse large B-cell lymphoma.

Conclusions: This study supports an association of current smoking with risk of NHL that varies by gender and subtype. Future studies should focus on differences by gender and disease subtype to better clarify the smoking and NHL relationship.
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http://dx.doi.org/10.1007/s10552-012-0001-3DOI Listing
August 2012

Inherited variation at chromosome 12p13.33, including RAD52, influences the risk of squamous cell lung carcinoma.

Cancer Discov 2012 Feb 7;2(2):131-9. Epub 2011 Dec 7.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Department of Health and Human Services, Bethesda, Maryland 20892, USA.

Unlabelled: Although lung cancer is largely caused by tobacco smoking, inherited genetic factors play a role in its etiology. Genome-wide association studies in Europeans have only robustly demonstrated 3 polymorphic variations that influence the risk of lung cancer. Tumor heterogeneity may have hampered the detection of association signal when all lung cancer subtypes were analyzed together. In a genome-wide association study of 5,355 European ever-smoker lung cancer patients and 4,344 smoking control subjects, we conducted a pathway-based analysis in lung cancer histologic subtypes with 19,082 single-nucleotide polymorphisms mapping to 917 genes in the HuGE-defined "inflammation" pathway. We identified a susceptibility locus for squamous cell lung carcinoma at 12p13.33 (RAD52, rs6489769) and replicated the association in 3 independent studies totaling 3,359 squamous cell lung carcinoma cases and 9,100 controls (OR = 1.20, P(combined) = 2.3 × 10(-8)).

Significance: The combination of pathway-based approaches and information on disease-specific subtypes can improve the identification of cancer susceptibility loci in heterogeneous diseases.
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http://dx.doi.org/10.1158/2159-8290.CD-11-0246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3354721PMC
February 2012