Showing papers by "Edward Giovannucci published in 2015"
TL;DR: Significant increases in overall prescription drug use and polypharmacy were observed in this nationally representative survey and persisted after accounting for changes in the age distribution of the population.
Abstract: Importance It is important to document patterns of prescription drug use to inform both clinical practice and research. Objective To evaluate trends in prescription drug use among adults living in the United States. Design, Setting, and Participants Temporal trends in prescription drug use were evaluated using nationally representative data from the National Health and Nutrition Examination Survey (NHANES). Participants included 37 959 noninstitutionalized US adults, aged 20 years and older. Seven NHANES cycles were included (1999-2000 to 2011-2012), and the sample size per cycle ranged from 4861 to 6212. Exposures Calendar year, as represented by continuous NHANES cycle. Main Outcomes and Measures Within each NHANES cycle, use of prescription drugs in the prior 30 days was assessed overall and by drug class. Temporal trends across cycles were evaluated. Analyses were weighted to represent the US adult population. Results Results indicate an increase in overall use of prescription drugs among US adults between 1999-2000 and 2011-2012 with an estimated 51% of US adults reporting use of any prescription drugs in 1999-2000 and an estimated 59% reporting use of any prescription drugs in 2011-2012 (difference, 8% [95% CI, 3.8%-12%]; P for trend P for trend Conclusions and Relevance In this nationally representative survey, significant increases in overall prescription drug use and polypharmacy were observed. These increases persisted after accounting for changes in the age distribution of the population. The prevalence of prescription drug use increased in the majority of, but not all, drug classes.
916 citations
TL;DR: The human population data may provide an impetus for further investigations on potential interactive roles of Fusobacterium and host immunity in colon carcinogenesis, and the amount of tissue F nucleatum is inversely associated with CD3+ T-cell density in colorectal carcinoma tissue.
Abstract: Importance Evidence indicates a complex link between gut microbiome, immunity, and intestinal tumorigenesis. To target the microbiota and immunity for colorectal cancer prevention and therapy, a better understanding of the relationship between microorganisms and immune cells in the tumor microenvironment is needed. Experimental evidence suggests thatFusobacterium nucleatummay promote colonic neoplasia development by downregulating antitumor T cell–mediated adaptive immunity. Objective To test the hypothesis that a greater amount ofF nucleatumin colorectal carcinoma tissue is associated with a lower density of T cells in tumor tissue. Design, Setting, and Participants A cross-sectional analysis was conducted on 598 rectal and colon carcinoma cases in 2 US nationwide prospective cohort studies with follow-up through 2006, the Nurses’ Health Study (participants enrolled in 1976) and the Health Professionals Follow-up Study (participants enrolled in 1986). Tissue collection and processing were performed from 2002 through 2008, and immunity assessment, 2008 through 2009. From 2013 through 2014, the amount ofF nucleatumin colorectal carcinoma tissue was measured by quantitative polymerase chain reaction assay; we equally dichotomized positive cases (high vs low). Multivariable ordinal logistic regression analysis was conducted in 2014 to assess associations of the amount ofF nucleatumwith densities (quartiles) of T cells in tumor tissue, controlling for clinical and tumor molecular features, including microsatellite instability, CpG island methylator phenotype, long interspersed nucleotide element-1 (LINE-1) methylation, andKRAS,BRAF, andPIK3CAmutation status. We adjusted the 2-sided α level to .013 for multiple hypothesis testing. Main Outcomes and Measures Densities of CD3+, CD8+, CD45RO (protein tyrosine phosphatase receptor type C [PTPRC])+, and FOXP3+T cells in tumor tissue, determined by means of tissue microarray immunohistochemical analysis and computer-assisted image analysis. Results F nucleatumwas detected in colorectal carcinoma tissue in 76 (13%) of 598 cases. Compared withF nucleatum–negative cases,F nucleatum–high cases were inversely associated with the density of CD3+T cells (for a unit increase in quartile categories of CD3+T cells as an outcome: multivariable odds ratio, 0.47 [95% CI, 0.26-0.87];Pfor trend = .006). The amount ofF nucleatumwas not significantly associated with the density of CD8+, CD45RO+, or FOXP3+T cells (P fortrend = .24, .88, and .014, respectively). Conclusions and Relevance The amount of tissueF nucleatumis inversely associated with CD3+T-cell density in colorectal carcinoma tissue. On validation, our human population data may provide an impetus for further investigations on potential interactive roles ofFusobacteriumand host immunity in colon carcinogenesis.
438 citations
TL;DR: Avoiding adult weight gain itself may confer protection against certain types of cancers, particularly among HRT nonusers.
Abstract: Backgrounds: Considerable evidence suggests that adiposity, measured by body mass index, is implicated in carcinogenesis. While adult weigh gain has diverse advantages over body mass index in measuring adiposity, systematic reviews on adult weight gain and risks of major cancers are lacking. Methods: PubMed and Embase were searched from the inception to May, 2014 to identify prospective observational studies investigating the relationship between adult weight gain and incident cancers of the breast, prostate, and colorectum. Dose-response meta-analyses were performed using a random-effects model to estimate summary relative risk (RR) and 95% confidence interval (CI) for each cancer type. Results: In the linear dose-response estimating cancer risk associated with 5kg increase in adult weight gain, a statistically significant direct association was found only for postmenopausal breast cancer and colon cancer. The summary RR was 1.11 (95% CI=1.08-1.13, I2=22%, seven studies with 4,570 cases, range=0-35kg) for postmenopausal breast cancer; 0.99 (95% CI=0.95-1.03, I2=36%, three studies with 2,409 cases, range=0-27.5kg) for premenopausal breast cancer. Etiologic heterogeneity by menopausal status at diagnosis was statistically significant (Pheterogeneity=0.001). The summary RR for colon cancer was 1.06 (95% CI=1.03-1.10, I2=0%, four studies with 2,909 cases, range=0-29kg). While there was no evidence of heterogeneity by sex (Pheterogeneity=0.17), the association was statistically significant only among men. No evidence of a linear association was indicated for prostate cancer (RR=0.98, 95% CI=0.94-1.02, four studies with 6,882 cases, range=0-25kg) and for its subtypes (localized: RR=0.96, 95% CI=0.92-1.00, I2=38%; advanced: RR=1.04, 95% CI=0.99-1.09, I2=0%). Conclusions: Avoiding adult weight gain itself may confer protection against postmenopausal breast cancer and colon cancer. As preventing weight gain is relatively more feasible than losing weight, clinicians and public health policies may prioritize weight maintenance throughout adulthood to reduce the burden of postmenopausal breast cancer and colon cancer.
303 citations
TL;DR: The prevalence of unsuspected prostate cancer discovered at autopsy among 6,024 men was reviewed, and among men aged 70–79, tumor was found in 36% of Caucasians and 51% of African‐Americans.
Abstract: Widespread prostate-specific antigen (PSA) screening detects many cancers that would have otherwise gone undiagnosed. To estimate the prevalence of unsuspected prostate cancer, we reviewed 19 studies of prostate cancer discovered at autopsy among 6,024 men. Among men aged 70-79, tumor was found in 36% of Caucasians and 51% of African-Americans. This enormous prevalence, coupled with the high sensitivity of PSA screening, has led to the marked increase in the apparent incidence of prostate cancer. The impact of PSA screening on clinical practice is well-recognized, but its effect on epidemiologic research is less appreciated. Before screening, a larger proportion of incident prostate cancers had lethal potential and were diagnosed at advanced stage. However, in the PSA era, overall incident prostate cancer mainly is indolent disease, and often reflects the propensity to be screened and biopsied. Studies must therefore focus on cancers with lethal potential, and include long follow-up to accommodate the lead time induced by screening. Moreover, risk factor patterns differ markedly for potentially lethal and indolent disease, suggesting separate etiologies and distinct disease entities. Studies of total incident or indolent prostate cancer are of limited clinical utility, and the main focus of research should be on prostate cancers of lethal potential.
202 citations
TL;DR: Light to moderate drinking is associated with minimally increased risk of overall cancer, and for men who have never smoked, risk of alcohol related cancers is not appreciably increased for light and moderate drinking (up to two drinks per day), however, for women who haveNever smoked,risk of alcoholrelated cancers increases even within the range of up to one alcoholic drink a day.
Abstract: ObjeCtives To quantify risk of overall cancer across all levels of alcohol consumption among women and men separately, with a focus on light to moderate drinking and never smokers; and assess the influence of drinking patterns on overall cancer risk. Design Two prospective cohort studies. s etting Health professionals in the United States. PartiC iPants 88 084 women and 47 881 men participating in the Nurses’ Health Study (from 1980) and Health Professionals Follow-up Study (from 1986), followed until 2010. Main Out COMes anD Measures Relative risks of cancer. results 19 269 and 7571 (excluding non-advanced prostate cancers) incident cancers were documented among women and men, respectively, over 3 144 853 person years. Compared with non-drinkers, light to moderate drinkers had relative risks of total cancer of 1.02 (95% confidence interval 0.98 to 1.06) and 1.04 (1.00 to 1.09; Ptrend=0.12) for alcohol intake of 0.1-4.9 and 5-14.9 g/day among women, respectively. Corresponding values for men were 1.03 (0.96 to 1.11), 1.05 (0.97 to 1.12), and 1.06 (0.98 to 1.15; Ptrend=0.31) for alcohol intake of 0.1-4.9, 5-14.9, and 15-29.9 g/day, respectively. Associations for light to moderate drinking and total cancer were similar among ever or never smokers, although alcohol consumption above moderate levels (in particular ≥30 g/day) was more strongly associated with risk of total cancer among ever smokers than never smokers. For a priori defined alcohol related cancers in men, risk was not appreciably increased for light and moderate drinkers who never smoked (Ptrend=0.18). However, for women, even an alcohol consumption of 5-14.9 g/day was associated with increased risk of alcohol related cancer (relative risk 1.13 (95% confidence interval 1.06 to 1.20)), driven by breast cancer. More frequent and heavy episodic drinking was not further associated with risk of total cancer after adjusting for total alcohol intake. COnClusiOn Light to moderate drinking is associated with minimally increased risk of overall cancer. For men who have never smoked, risk of alcohol related cancers is not appreciably increased for light and moderate drinking (up to two drinks per day). However, for women who have never smoked, risk of alcohol related cancers (mainly breast cancer) increases even within the range of up to one alcoholic drink a day.
191 citations
Indiana University1, National Institutes of Health2, Fred Hutchinson Cancer Research Center3, American Cancer Society4, University of Utah5, University of Washington6, University of North Carolina at Chapel Hill7, German Cancer Research Center8, Kaiser Permanente9, University of Southern California10, Cancer Care Ontario11, Translational Genomics Research Institute12, Harvard University13, New York University14, University of Melbourne15, Ontario Institute for Cancer Research16, University of Toronto17, Mayo Clinic18, University of Hawaii at Manoa19, Massey University20, University of Pittsburgh21, University of Tennessee Health Science Center22, Ottawa Hospital Research Institute23
TL;DR: In this genome-wide investigation of gene × environment interactions, use of aspirin and/or NSAIDs was associated with lower risk of colorectal cancer, and this association differed according to genetic variation at 2 SNPs at chromosomes 12 and 15.
Abstract: Importance Use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with lower risk of colorectal cancer. Objective To identify common genetic markers that may confer differential benefit from aspirin or NSAID chemoprevention, we tested gene × environment interactions between regular use of aspirin and/or NSAIDs and single-nucleotide polymorphisms (SNPs) in relation to risk of colorectal cancer. Design, Setting, and Participants Case-control study using data from 5 case-control and 5 cohort studies initiated between 1976 and 2003 across the United States, Canada, Australia, and Germany and including colorectal cancer cases (n=8634) and matched controls (n=8553) ascertained between 1976 and 2011. Participants were all of European descent. Exposures Genome-wide SNP data and information on regular use of aspirin and/or NSAIDs and other risk factors. Main Outcomes and Measures Colorectal cancer. Results Regular use of aspirin and/or NSAIDs was associated with lower risk of colorectal cancer (prevalence, 28% vs 38%; odds ratio [OR], 0.69 [95% CI, 0.64-0.74]; P = 6.2 × 10 −28 ) compared with nonregular use. In the conventional logistic regression analysis, the SNP rs2965667 at chromosome 12p12.3 near the MGST1 gene showed a genome-wide significant interaction with aspirin and/or NSAID use ( P = 4.6 × 10 −9 for interaction). Aspirin and/or NSAID use was associated with a lower risk of colorectal cancer among individuals with rs2965667-TT genotype (prevalence, 28% vs 38%; OR, 0.66 [95% CI, 0.61-0.70]; P = 7.7 × 10 −33 ) but with a higher risk among those with rare (4%) TA or AA genotypes (prevalence, 35% vs 29%; OR, 1.89 [95% CI, 1.27-2.81]; P = .002). In case-only interaction analysis, the SNP rs16973225 at chromosome 15q25.2 near the IL16 gene showed a genome-wide significant interaction with use of aspirin and/or NSAIDs ( P = 8.2 × 10 −9 for interaction). Regular use was associated with a lower risk of colorectal cancer among individuals with rs16973225-AA genotype (prevalence, 28% vs 38%; OR, 0.66 [95% CI, 0.62-0.71]; P = 1.9 × 10 −30 ) but was not associated with risk of colorectal cancer among those with less common (9%) AC or CC genotypes (prevalence, 36% vs 39%; OR, 0.97 [95% CI, 0.78-1.20]; P = .76). Conclusions and Relevance In this genome-wide investigation of gene × environment interactions, use of aspirin and/or NSAIDs was associated with lower risk of colorectal cancer, and this association differed according to genetic variation at 2 SNPs at chromosomes 12 and 15. Validation of these findings in additional populations may facilitate targeted colorectal cancer prevention strategies.
165 citations
Joshua N. Sampson1, William Wheeler, Meredith Yeager1, Orestis A. Panagiotou1 +445 more•Institutions (113)
TL;DR: Correlation analysis indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the Genetic etiology for the same disease can vary by population and environmental exposures.
Abstract: Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the add ...
158 citations
TL;DR: PTEN loss is independently associated with increased risk of lethal progression, particularly in the ERG fusion-negative subgroup, and these validated and inexpensive IHC assays may be useful for risk stratification in prostate cancer.
Abstract: Background PTEN is a tumor suppressor frequently deleted in prostate cancer that may be a useful prognostic biomarker. However, the association of PTEN loss with lethal disease has not been tested in a large, predominantly surgically treated cohort. Methods In the Health Professionals Follow-up Study and Physicians' Health Study, we followed 1044 incident prostate cancer cases diagnosed between 1986 and 2009 for cancer-specific and all-cause mortality. A genetically validated PTEN immunohistochemistry (IHC) assay was performed on tissue microarrays (TMAs). TMPRSS2:ERG status was previously assessed in a subset of cases by a genetically validated IHC assay for ERG. Cox proportional hazards models adjusting for age and body mass index at diagnosis, Gleason grade, and clinical or pathologic TNM stage were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association with lethal disease. All statistical tests were two-sided. Results On average, men were followed 11.7 years, during which there were 81 lethal events. Sixteen percent of cases had complete PTEN loss in all TMA cores and 9% had heterogeneous PTEN loss across cores. After adjustment for clinical-pathologic variables, complete PTEN loss was associated with lethal progression (HR = 1.8, 95% CI = 1.2 to 2.9). The association of PTEN loss (complete or heterogeneous) with lethal progression was only among men with ERG-negative (HR = 3.1, 95% CI = 1.7 to 5.7) but not ERG-positive (HR = 1.2, 95% CI = 0.7 to 2.2) tumors. Conclusions PTEN loss is independently associated with increased risk of lethal progression, particularly in the ERG fusion-negative subgroup. These validated and inexpensive IHC assays may be useful for risk stratification in prostate cancer.
156 citations
TL;DR: An expanded, integrative concept, ‘etiologic field effect’, is explored, which asserts that various etiologic factors and their interactions contribute to a tissue microenvironmental milieu that constitutes a ‘field of susceptibility’ to neoplasia initiation, evolution, and progression.
152 citations
TL;DR: Aspirin and COX-2 inhibitor use may be associated with improved outcomes in stage III colon cancer patients and Adjusted HRs for RFS, DFS, and OS censored at five years were 0.61 (95% CI = 0.36 to 1.04) and 0.48 (95%) for DFS censored atFive years.
Abstract: We conducted a prospective, observational study of aspirin and COX-2 inhibitor use and survival in stage III colon cancer patients enrolled in an adjuvant chemotherapy trial. Among 799 eligible patients, aspirin use was associated with improved recurrence-free survival (RFS) (multivariable hazard ratio [HR] = 0.51, 95% confidence interval [CI] = 0.28 to 0.95), disease-free survival (DFS) (HR = 0.68, 95% CI = 0.42 to 1.11), and overall survival (OS) (HR = 0.63, 95% CI = 0.35 to 1.12). Adjusted HRs for DFS and OS censored at five years (in an attempt to minimize misclassification from noncancer death) were 0.61 (95% CI = 0.36 to 1.04) and 0.48 (95% CI = 0.23 to 0.99). Among 843 eligible patients, those who used COX-2 inhibitors had multivariable HRs for RFS, DFS, and OS of 0.53 (95% CI = 0.27 to 1.04), 0.60 (95% CI = 0.33 to 1.08), and 0.50 (95% CI = 0.23 to 1.07), and HRs of 0.47 (95% CI = 0.24 to 0.91) and 0.26 (95% CI = 0.08 to 0.81) for DFS and OS censored at five years. Aspirin and COX-2 inhibitor use may be associated with improved outcomes in stage III colon cancer patients.
119 citations
TL;DR: The risk of high-grade cervical dysplasia and cervical cancer was 1.5 times higher in women with RA and SLE than in those without SID, and the risk may be increased in IBD with use of systemic immunosuppressive drugs or steroids.
Abstract: Background Previous studies have suggested a potential risk of cervical cancer in patients with systemic inflammatory diseases (SID) such as inflammatory bowel disease (IBD) and systemic lupus erythematosus (SLE). Objectives To assess the risk of high-grade cervical dysplasia, a surrogate endpoint for cervical cancer and cervical cancer, in women with SID, including IBD, psoriasis, rheumatoid arthritis (RA) or SLE, compared with the risk in women without SID. Methods Using US insurance data (2001–2012), we conducted a cohort study of 133 333 women with SID, based on two or more diagnoses and one or more dispensed prescription for disease-specific treatment, and 533 332 women without SID. High-grade cervical dysplasia and cervical cancer was defined by a validated algorithm with a positive predictive value of ≥81%. Results Over the mean follow-up of 2.1 years, the crude incidence rate of high-grade cervical dysplasia and cervical cancer per 100 000 person-years was the highest at 141.1 in SLE and the lowest at 82.2 in psoriasis among women with SID, and 73.4 in women without SID. The multivariable HR adjusted for potential confounders was 1.07 (95% CI 0.79 to 1.45) in IBD, 0.96 (95% CI 0.73 to 1.27) in psoriasis, 1.49 (95% CI 1.11 to 2.00) in RA and 1.53 (95% CI 1.07 to 2.19) in SLE. Multivariable HRs were increased, but not statistically significant, in IBD, RA and SLE with baseline use of systemic immunosuppressive drugs or steroids. Conclusions The risk of high-grade cervical dysplasia and cervical cancer was 1.5 times higher in women with RA and SLE than in those without SID. The risk may be increased in IBD with use of systemic immunosuppressive drugs or steroids.
TL;DR: In these two large cohorts of US health professionals, processed red meat intake was positively associated with risk of CRC, particularly distal cancer, with little evidence that higher intake of unprocessed red meat substantially increasedrisk of CRC.
Abstract: Although the association between red meat consumption and colorectal cancer (CRC) is well established, the association across subsites of the colon and rectum remains uncertain, as does time of consumption in relation to cancer development. As these relationships are key for understanding the pathogenesis of CRC, they were examined in two large cohorts with repeated dietary measures over time, the Nurses’ Health Study (n = 87,108 women, 1980–2010) and Health Professionals Follow-up Study (n = 47,389 men, 1986–2010). Cox proportional hazards regression models generated hazard ratios (HRs) and 95% confidence intervals (CIs), which were pooled by random-effects meta-analysis. In combined cohorts, there were 2,731 CRC cases (1,151 proximal colon, 816 distal colon, and 589 rectum). In pooled analyses, processed red meat was positively associated with CRC risk (per 1 serving/day increase: HR = 1.15, 95% CI: 1.01–1.32; P for trend 0.03) and particularly with distal colon cancer (per 1 serving/day increase; HR = 1.36; 95% CI: 1.09–1.69; P for trend 0.006). Recent consumption of processed meat (within the past 4 years) was not associated with distal cancer. Unprocessed red meat was inversely associated with risk of distal colon cancer and a weak non-significant positive association between unprocessed red meat and proximal cancer was observed (per 1 serving/day increase: distal HR = 0.75; 95% CI: 0.68–0.82; P for trend <0.001; proximal HR = 1.14, 95% CI: 0.92–1.40; P for trend 0.22). Thus, in these two large cohorts of US health professionals, processed meat intake was positively associated with risk of CRC, particularly distal cancer, with little evidence that higher intake of unprocessed red meat substantially increased risk of CRC. Future studies, particularly those with sufficient sample size to assess associations by subsites across the colon are needed to confirm these findings and elucidate potentially distinct mechanisms underlying the relationship between processed meat and subtypes of unprocessed red meat with CRC.
TL;DR: Being obese prior to diagnosis of colorectal cancer was associated with increased coloreCTal cancer-specific mortality and all-cause mortality, whereas being obese after diagnosis wasassociated with increased all- cause mortality.
Abstract: Studies have reported conflicting results on the association between body mass index (BMI) and prognosis of colorectal cancer. Therefore, we have conducted a meta-analysis of prospective studies, which examined the association of pre- and post-diagnostic BMI with colorectal cancer-specific mortality and all-cause mortality in patients with colorectal cancer. We searched Medline and EMBASE database published between 1970 and September 2014. A total of 508 articles were identified, of which 16 prospective cohort studies were included for the current meta-analysis. The analysis included 58,917 patients who were followed up over a period ranging from 4.9 to 20 years (median: 9.9 years). We found that being underweight before cancer diagnosis was associated with increased all-cause mortality (Relative risk [RR]: 1.63, 95% CI: 1.18–2.23, p < 0.01) and being obese (BMI ≥ 30 kg/m2) before cancer diagnosis was associated with increased colorectal cancer-specific mortality (RR: 1.22, 95% CI: 1.003–1.35, p < 0.01) and all-cause mortality (RR: 1.25, 95% CI: 1.14–1.36, p < 0.01). On the other hand, being underweight (RR: 1.33, 95% CI: 1.20–1.47, p < 0.01), obese (RR: 1.08, 95% CI: 1.03–1.3, p < 0.01), and class II/III obese (BMI ≥ 35 kg/m2; RR: 1.13, 95% CI: 1.04–1.23, p < 0.01) after diagnosis were associated with significantly increased all-cause mortality. Being obese prior to diagnosis of colorectal cancer was associated with increased colorectal cancer-specific mortality and all-cause mortality, whereas being obese after diagnosis was associated with increased all-cause mortality. The associations with being underweight may reflect reverse causation. Maintaining a healthy body weight should be discussed with colorectal cancer survivors.
Cancer Epidemiology Unit1, Johns Hopkins University2, Medical University of South Carolina3, University Medical Center Utrecht4, Imperial College London5, University of California, San Francisco6, University of Bristol7, Sorbonne8, Cancer Council Victoria9, Brigham and Women's Hospital10, Harvard University11, University of Washington12, National Institutes of Health13, Mercy Medical Center (Baltimore, Maryland)14, University of Southern California15, Umeå University16, International Agency for Research on Cancer17, University of Cambridge18, Core Laboratories19, University of New Mexico20, University of Hawaii21, National Institute for Health Research22, Norwegian Institute of Public Health23, Prevention Institute24, Fred Hutchinson Cancer Research Center25, Academy of Athens26, Clinical Trial Service Unit27
TL;DR: In this paper, Carotenoids, retinol, or tocopherols may be associated with prostate cancer risk, but the studies have not been large enough to provid...
TL;DR: A large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population.
Abstract: Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 × 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population.
TL;DR: Calcium may not have a strong independent effect on prostate cancer risk except with long latency periods, and phosphorus is independently associated with risk of lethal and high-grade prostate cancer.
19 Feb 2015
TL;DR: Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
TL;DR: Long-standing diabetes was associated with statistically significantly decreased survival among patients with pancreatic cancer enrolled onto three longitudinal studies.
Abstract: Purpose Long-standing diabetes is a risk factor for pancreatic cancer, and recent-onset diabetes in the several years before diagnosis is a consequence of subclinical pancreatic malignancy. However, the impact of diabetes on survival is largely unknown. Patients and Methods We analyzed survival by diabetes status among 1,006 patients diagnosed from 1986 to 2010 from two prospective cohort studies: the Nurses' Health Study (NHS) and Health Professionals Follow-Up Study (HPFS). We validated our results among 386 patients diagnosed from 2004 to 2013 from a clinic-based case series at Dana-Farber Cancer Institute (DFCI). We estimated hazard ratios (HRs) for death using Cox proportional hazards models, with adjustment for age, sex, race/ethnicity, smoking, diagnosis year, and cancer stage. Results In NHS and HPFS, HR for death was 1.40 (95% CI, 1.15 to 1.69) for patients with long-term diabetes (> 4 years) compared with those without diabetes (P < .001), with median survival times of 3 months for long-term dia...
TL;DR: The observed inverse association between aspirin use and liver cancer in this study, together with previous data, suggests the merit of future intervention studies of aspirin and other agents that affect chronic inflammatory pathways for HCC and possibly ICC.
Abstract: Chronic inflammation plays a pivotal role in the pathogenesis of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), the two most common types of liver cancer. A number of prior experimental studies have suggested that non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin and ibuprofen, may potentially protect against liver cancer. However, no observational study has examined the association between aspirin duration and dose or other over-the-counter non-aspirin NSAIDs, such as ibuprofen, and liver cancer incidence. Furthermore, the association between NSAID use and risk of ICC is unclear. As part of the Liver Cancer Pooling Project, we harmonized data on 1,084,133 individuals (HCC=679, ICC=225) from ten US-based prospective cohort studies. Cox proportional hazards regression models were used to evaluate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Current aspirin use, versus nonuse, was inversely associated with HCC (HR=0.68, 95% CI=0.57-0.81), which persisted when restricted to individuals not using non-aspirin NSAIDs and in a 5 and 10-year lag analysis. The association between aspirin use and HCC risk was stronger for users who reported daily use, longer duration use, and lower dosage. Ibuprofen use was not associated with HCC risk. Aspirin use was associated with a reduced ICC risk in men (HR=0.64, 95% CI=0.42-0.98) but not women (HR=1.34, 95% CI=0.89-2.01, pinteraction=0.01). The observed inverse association between aspirin use and liver cancer in our study, together with previous data, suggest the merit of future intervention studies of aspirin and other agents that affect chronic inflammatory pathways for HCC and possibly ICC.
TL;DR: The findings support the growing evidence that early life body fatness affects the risk of colorectal cancer many decades later, and might be a risk factor for coloreCTal cancer in women but there is a weaker association in men.
Abstract: Background: The association between body fatness before adulthood and later risk of colorectal cancer remains unclear. We hypothesized that, independent of adult body fatness, early life body fatness would be associated with a higher risk of developing colorectal cancer.
Methods: We assessed body fatness during childhood and adolescence using a validated 9-level somatotype and inquired body weight in young adulthood in the Nurses' Health Study and Health Professionals Follow-up Study. We used the Cox proportional hazard regression modeling to estimate relative risks [RR, 95% confidence intervals (CI)] adjusting for adult body mass index (BMI) and other known colorectal cancer risk factors.
Results: We identified 2,100 incident colorectal cancer cases (1,292 in women and 808 in men) during 22 years of follow-up. Among women, the RR (95% CI) for childhood body fatness of level 5 or higher versus level 1 was 1.28 (1.04–1.58; P trend = 0.08) and for adolescent body fatness, it was 1.27 (1.01–1.60; P trend = 0.23). The corresponding RRs for men were 1.04 (0.82–1.31; P trend = 0.48) and 0.98 (0.75–1.27; P trend = 0.20), respectively. Results were generally similar across anatomic subsites within the colorectum. In addition, the RRs comparing BMI categories ≥27.5 to <19 kg/m2 were 1.44 (1.06–1.95, at age 18; P trend = 0.009) for women and 1.18 (0.84–1.65, at age 21; P trend = 0.57) for men.
Conclusion: Increased body fatness in early life, independent of adult obesity, might be a risk factor for colorectal cancer in women, but we observed a weaker association in men.
Impact: Our findings support the growing evidence that early life body fatness affects the risk of colorectal cancer many decades later. Cancer Epidemiol Biomarkers Prev; 24(4); 1–8. ©2015 AACR .
TL;DR: In this prospective study, longer LTL was modestly associated with higher risk of prostate cancer and a stronger association for more aggressive cancer in men with a family history of the disease needs to be confirmed in larger studies.
Abstract: Recent large-scale prospective studies suggest that long telomeres are associated with an increase cancer risk, counter to conventional wisdom. To further clarify the association between leukocyte telomere length (LTL) and prostate cancer, and assess genetic variability in relation to both LTL and prostate cancer, we performed a nested case–control study (922 cases and 935 controls). The participants provided blood in 1993–1995 and were followed through August 2004 (prostate cancer incidence) or until 28 February 2013 (lethal or fatal prostate cancer). Relative LTL was measured by quantitative PCR and was calculated as the ratio of telomere repeat copy number to a single gene (36B4) copy number (T/S). Genotyping was performed using the TaqMan OpenArray SNP Genotyping Platform. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of all prostate cancer and subtypes defined by Gleason grade, stage and lethality (metastasis or death). We observed a positive association between each s.d. increase in LTL and all (multivariable-adjusted OR 1.11, 95% CI: 1.01–1.22), low-grade (OR 1.13, 95% CI:1.01–1.27), and localised (OR 1.12, 95% CI:1.01–1.24) prostate cancer. Associations for other subtypes were similar, but did not reach statistical significance. In subgroup analyses, associations for high grade and advanced stage (OR=2.04, 95% CI 1.00–4.17; Pinteraction=0.06) or lethal disease (OR=2.37, 95% CI 1.19–4.72; Pinteraction=0.01) were stronger in men with a family history of the disease compared with those without. The minor allele of SNP, rs7726159, which has previously been shown to be positively associated with LTL, showed an inverse association with all prostate cancer risk after correction for multiple testing (P=0.0005). In this prospective study, longer LTL was modestly associated with higher risk of prostate cancer. A stronger association for more aggressive cancer in men with a family history of the disease needs to be confirmed in larger studies.
TL;DR: V VAT may be the underlying mediator of the observed associations of BMI and WC with adenomas, increasing adenoma risk continuously over a wide range of VAT area.
TL;DR: Being low in IGFBP‐1 or high in IGF‐1 is sufficient to elevate the risk of prostate cancer, and prediagnostic fasting IGF BP‐1 may influence prostate cancer carcinogenesis.
Abstract: Insulin-like growth factor (IGF)-1 is associated with a higher risk of prostate cancer. IGF-binding protein (IGFBP)-1, a marker for insulin activity, also binds IGF-1 and inhibits its action. Data on IGFBP-1 and prostate cancer risk are sparse and whether the IGF and insulin axes interact to affect prostate cancer carcinogenesis is unknown. We evaluated the independent and joint influence of prediagnostic plasma levels of IGFBP-1 (fasting) and IGF-1 on risk of prostate cancer among 957 cases and 1,021 controls with fasting levels of IGFBP-1 and 1,709 cases and 1,778 controls with IGF-1 nested within the Health Professionals Follow-up Study. Unconditional logistic regression adjusting for matching factors was used to estimate the odds ratio (OR) and 95% confidence interval (CI). Higher prediagnostic fasting IGFBP-1 levels were associated with lower risk of prostate cancer (highest vs. lowest quartile OR = 0.67, 95% CI 0.52-0.86, ptrend = 0.003), which remained similar after adjusting for IGF-1. Prediagnostic IGF-1 was associated with increased risk of prostate cancer (highest vs. lowest quartile OR = 1.28, 95% CI = 1.05-1.56, ptrend = 0.01). The associations with each marker were primarily driven by lower-grade and non-advanced prostate cancer. Being low in IGFBP-1 and high in IGF-1 did not confer appreciable additional risk (pinteraction = 0.42). In summary, prediagnostic fasting IGFBP-1 may influence prostate cancer carcinogenesis. Being low in IGFBP-1 or high in IGF-1 is sufficient to elevate the risk of prostate cancer.
Memorial Sloan Kettering Cancer Center1, National Institutes of Health2, University of California, Berkeley3, Mayo Clinic4, Stanford University5, Statens Serum Institut6, Uppsala University7, Karolinska Institutet8, University of California, San Francisco9, Harvard University10, City of Hope National Medical Center11, University of British Columbia12, Simon Fraser University13, Utrecht University14, University of Iowa15, University of North Carolina at Chapel Hill16, University of Texas MD Anderson Cancer Center17, University of Southern California18, German Cancer Research Center19, American Cancer Society20, Macquarie University21, Yale University22, University of Melbourne23, Cancer Council Victoria24, Imperial College London25, New York University26, University of Cagliari27, University of York28, Dalian Maritime University29, Ohio State University30, Fred Hutchinson Cancer Research Center31, Drexel University32, Wayne State University33, Icahn School of Medicine at Mount Sinai34, International Agency for Research on Cancer35, University of Burgundy36, Dublin City University37, University of New South Wales38, University of Sydney39, University of Bari40, National Institute for Health and Welfare41, University of Chicago42, University of Freiburg43
TL;DR: This work identifies two independent loci near BTNL2 and HLA-B in the HLA region significantly associated with MZL risk and finds the first evidence that genetic variation in the major histocompatibility complex influences MzL susceptibility.
Abstract: 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.
TL;DR: Prehospital 25(OH)D was associated with the risk of acute respiratory failure in the authors' critically ill patient cohort, and patients with lower 25( OH)D levels had significantly higher adjusted odds of acute lungs failure.
Abstract: Objective: We hypothesise that low 25-hydroxyvitamin D (25(OH)D) levels before hospitalisation are associated with increased risk of acute respiratory failure. Design: Retrospective cohort study. Setting: Medical and Surgical Intensive care units of two Boston teaching hospitals. Patients: 1985 critically ill adults admitted between 1998 and 2011. Interventions: None. Measurements and main results: The exposure of interest was prehospital serum 25(OH)D categorised as ≤10 ng/mL, 11–19.9 ng/mL, 20–29.9 ng/mL and ≥30 ng/mL. The primary outcome was acute respiratory failure excluding congestive heart failure determined by International Classification of Diseases Ninth Edition (ICD-9) coding and validated against the Berlin Definition of acute respiratory sistress syndrome. Association between 25(OH)D and acute respiratory failure was assessed using logistic regression, while adjusting for age, race, sex, Deyo-Charlson Index and patient type (medical vs surgical). In the cohort, the mean age was 63 years, 45% were male and 80% were white; 25(OH)D was ≤10 ng/mL in 8% of patients, 11–19.9 ng/mL in 24%, 20–29.9 ng/mL in 24% and ≥30 ng/mL in 44% of patients. Eighteen per cent (n=351) were diagnosed with acute respiratory failure. Compared to patients with 25(OH)D ≥30 ng/mL, patients with lower 25(OH)D levels had significantly higher adjusted odds of acute respiratory failure (≤10 ng/mL, OR=1.84 (95% CI 1.22 to 2.77); 11–19.9 ng/mL, OR=1.60 (95% CI 1.19 to 2.15); 20–29.9 ng/mL, OR=1.37 (95% CI 1.01 to 1.86)). Conclusions: Prehospital 25(OH)D was associated with the risk of acute respiratory failure in our critically ill patient cohort.
TL;DR: Higher coffee intake may be associated with significantly reduced cancer recurrence and death in patients with stage III colon cancer, and the association of total coffee intake with improved outcomes seemed consistent across other predictors of cancerRecurrence and mortality.
Abstract: Purpose Observational studies have demonstrated increased colon cancer recurrence in states of relative hyperinsulinemia, including sedentary lifestyle, obesity, and increased dietary glycemic load. Greater coffee consumption has been associated with decreased risk of type 2 diabetes and increased insulin sensitivity. The effect of coffee on colon cancer recurrence and survival is unknown. Patients and Methods During and 6 months after adjuvant chemotherapy, 953 patients with stage III colon cancer prospectively reported dietary intake of caffeinated coffee, decaffeinated coffee, and nonherbal tea, as well as 128 other items. We examined the influence of coffee, nonherbal tea, and caffeine on cancer recurrence and mortality using Cox proportional hazards regression. Results Patients consuming 4 cups/d or more of total coffee experienced an adjusted hazard ratio (HR) for colon cancer recurrence or mortality of 0.58 (95% CI, 0.34 to 0.99), compared with never drinkers (Ptrend = .002). Patients consuming 4 c...
TL;DR: Assessment of associations of circulating 25‐hydroxyvitamin D (25(OH)D) and common variations in key vitamin D–related genes with fatal PCa found that there may be a benefit for survival.
Abstract: BACKGROUND
Evidence from experimental animal and cell line studies supports a beneficial role for vitamin D in prostate cancer (PCa). Although the results from human studies have been mainly null for overall PCa risk, there may be a benefit for survival. This study assessed the associations of circulating 25-hydroxyvitamin D (25(OH)D) and common variations in key vitamin D–related genes with fatal PCa.
METHODS
In a large cohort consortium, 518 fatal cases and 2986 controls with 25(OH)D data were identified. Genotyping information for 91 single-nucleotide polymorphisms (SNPs) in 7 vitamin D–related genes (vitamin D receptor, group-specific component, cytochrome P450 27A1 [CYP27A1], CYP27B1, CYP24A1, CYP2R1, and retinoid X receptor α) was available for 496 fatal cases and 3577 controls. Unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the associations of 25(OH)D and SNPs with fatal PCa. The study also tested for 25(OH)D-SNP interactions among 264 fatal cases and 1169 controls.
RESULTS
No statistically significant relationship was observed between 25(OH)D and fatal PCa (OR for extreme quartiles, 0.86; 95% CI, 0.65-1.14; P for trend = .22) or the main effects of the SNPs and fatal PCa. There was evidence suggesting that associations of several SNPs, including 5 related to circulating 25(OH)D, with fatal PCa were modified by 25(OH)D. Individually, these associations did not remain significant after multiple testing; however, the P value for the set-based test for CYP2R1 was .002.
CONCLUSIONS
Statistically significant associations were not observed for either 25(OH)D or vitamin D–related SNPs with fatal PCa. The effect modification of 25(OH)D associations by biologically plausible genetic variation may deserve further exploration. Cancer 2015;121:1949–1956. © 2015 American Cancer Society.
TL;DR: This study examined prospectively whether weight training, moderate to vigorous aerobic activity (MVAA), and replacement of one activity for another were associated with favorable changes in WC and body weight.
Abstract: Objective
Findings on weight training and waist circumference (WC) change are controversial. This study examined prospectively whether weight training, moderate to vigorous aerobic activity (MVAA), and replacement of one activity for another were associated with favorable changes in WC and body weight (BW).
Methods
Physical activity, WC, and BW were reported in 1996 and 2008 in a cohort of 10,500 healthy U.S. men in the Health Professionals Follow-up Study. Multiple linear regression models (partition/substitution) to assess these associations were used.
Results
After adjusting for potential confounders, a significant inverse dose-response relationship between weight training and WC change (P-trend <0.001) was observed. Less age-associated WC increase was seen with a 20-min/day activity increase; this benefit was significantly stronger for weight training (−0.67 cm, 95% CI −0.93, −0.41) than for MVAA (−0.33 cm, 95% CI −0.40, −0.27), other activities (−0.16 cm, 95% CI −0.28, −0.03), or TV watching (0.08 cm, 95% CI 0.05, 0.12). Substituting 20 min/day of weight training for any other discretionary activity had the strongest inverse association with WC change. MVAA had the strongest inverse association with BW change (−0.23 kg, 95% CI −0.29, −0.17).
Conclusions
Among various activities, weight training had the strongest association with less WC increase. Studies on frequency/volume of weight training and WC change are warranted.
TL;DR: In this cohort of healthy women, a significant inverse association between prediagnostic 25(OH)D levels and risk of incident colorectal cancer is found, and a borderline significant inverse associations betweenprediagnostics 25( OH)D Levels and coloreCTal cancer-related mortality are observed.
Abstract: Observational data on the association between circulating 25(OH)D and colorectal cancer risk are limited in women To determine whether prediagnostic levels of 25(OH)D were associated with risk of incident colorectal cancer in the Women's Health Study (WHS), we conducted a nested case-control study using 274 colorectal cases and 274 controls Each case was matched to a control by age, ethnicity, fasting status at the time of blood collection, time of day when blood was drawn, and month of blood draw Conditional logistic regression was used to estimate the OR and 95% confidence interval (CI) for colorectal cancer by 25(OH)D quartiles Mean plasma 25(OH)D was lower in cases versus controls (219 vs 239 ng/mL, P = 001) In multivariable-adjusted logistic regression models, plasma 25(OH)D was significantly and inversely associated with odds of colorectal cancer (quartile 4 [Q4] vs quartile 1 [Q1]: OR, 045; 95% CI, 025-081; Ptrend 002) In addition, we observed a somewhat lower risk of colorectal cancer-related mortality after adjustment for matching variables, randomization treatment and other risk factors (Q4:Q1 OR, 040; 95% CI, 017-097; Ptrend 005) In this cohort of healthy women, we found a significant inverse association between prediagnostic 25(OH)D levels and risk of incident colorectal cancer, and a borderline significant inverse association between prediagnostic 25(OH)D levels and colorectal cancer-related mortality These results support a possible association between plasma 25(OH)D and risk of colorectal cancer in women
TL;DR: Independent of adiposity, higher levels of insulin, C-peptide, and HOMA-IR were significantly associated with increased risk of CRA, indicating that insulin resistance and hyperinsulinemia may contribute in part to the association between obesity and CRA risk.
Abstract: Background Insulin stimulates cell proliferation and inhibits apoptosis. While epidemiologic studies have investigated associations between markers of insulin resistance/hyperinsulinemia (i.e., circulating insulin, homeostasis model assessment-insulin resistance (HOMA-IR), C-peptide) and risk of colorectal adenoma (CRA), the effect size has not yet been quantified. Objective We aimed to summarize the association between hyperinsulinemia/insulin resistance and risk of CRA, including whether the association is independent of adiposity. Materials and Methods Pubmed and Embase were searched through April, 2015 to identify observational studies investigating the associations between insulin, C-peptide and HOMA-IR and CRA risk. Using the highest versus lowest category meta-analysis and dose–response meta-analysis based on a random-effects model, we estimated summary odds ratio (OR) and the corresponding 95% confidence interval (95% CI). Results A total of 27 studies (insulin: 16 studies including 14,007 cases; C-peptide: 11 studies including 8639 cases; HOMA-IR: 8 studies including 11,619 cases) were included in this meta-analysis. The summary ORs of CRA comparing the highest with the lowest quantile were 1.33 for insulin (95% CI=1.12–1.58, I 2 =73.9%, P heterogeneity 2 =63.5%, P heterogeneity =0.003), and 1.33 for HOMA-IR (95% CI=1.10–1.60, I 2 =69.1%, P heterogeneity =0.004). Upon stratification by ethnicity, higher levels of insulin and C-peptide were significantly associated with increased risk of CRA in non-Asian ethnicity (summary OR for insulin=1.67 [95% CI=1.28–2.17], I 2 =34.9%, P heterogeneity =0.16; summary OR for C-peptide=1.59 [95% CI=1.22–2.08], I 2 =21.5%, P heterogeneity =0.27) but not in Asians (summary OR for insulin=1.10 [95% CI=0.92–1.33], I 2 =76.6%, P heterogeneity =0.001; summary OR for C-peptide=1.27 [95% CI=0.84–1.91], I 2 =72.6, P heterogeneity =0.01). We observed evidence for the existence of publication bias for insulin (P=0.01 by Egger test) and HOMA-IR (P=0.05 by Egger test). The results were confirmed in linear dose–response meta-analysis. These significant positive associations generally persisted even after adjustment for adiposity, although the effect size was substantially attenuated. Conclusions Independent of adiposity, higher levels of insulin, C-peptide, and HOMA-IR were significantly associated with increased risk of CRA. The weaker associations and high heterogeneity in Asian studies warrant further research. These results indicate that insulin resistance and hyperinsulinemia may contribute in part to the association between obesity and CRA risk.