Chlorinated solvents are classified as probable or possible carcinogens. It is unknown whether exposure to these agents increases the risk of malignant or benign brain tumors. Our objective was to evaluate associations of brain tumor risk with occupational exposure to six chlorinated solvents [i.e., dichloromethane, chloroform, carbon tetrachloride, 1,1,1-trichloroethane, trichloroethylene, and perchloroethylene].
489 glioma cases, 197 meningioma cases, and 799 controls were enrolled in a hospital-based case-control study conducted at three U.S. hospitals in Arizona, Massachusetts and Pennsylvania. Information about occupational history was obtained through a detailed in-person interview that included job-specific modules of questions such that the interview was tailored to each individual’s particular work history. An industrial hygienist assessed potential solvent exposure based on this information and an exhaustive review of the relevant industrial hygiene literature. Unconditional logistic regression models were used to calculate odds ratios (OR) and 95% confidence intervals (95%CI) for each solvent for ever/never, duration, cumulative, average weekly, and highest exposure.
Overall, we found no consistent evidence of an increased risk of glioma or meningioma related to occupational exposure to the six chlorinated solvents evaluated. There was some suggestion of an association between carbon tetrachloride and glioma in analyses restricted to exposed subjects, with average weekly exposure above the median associated with increased risk compared to below-median exposure (OR=7.1, 95%CI: 1.1, 45.2).
We found no consistent evidence for increased brain tumor risk related to chlorinated solvents.
epidemiology; cancer; solvents
Obesity is a risk factor for renal cell (or renal) cancer. The increasing prevalence of obesity may be contributing to the rising incidence of this cancer over the past several decades. The effects of early-age obesity and change in body mass index (BMI) on renal cancer have been studied less thoroughly, and the influence of race has never been formally investigated.
Using data gathered as part of a large case-control study of renal cancer (1,214 cases and 1,234 controls), we investigated associations with BMI at several time points, as well as with height. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were computed using logistic regression modeling. Race- and sex-stratified analyses were conducted to evaluate subgroup differences.
Obesity (BMI ≥ 30 kg/m2) early in adulthood (OR=1.6 [95% CI=1.1 to 2.4]) and 5 years before diagnosis (1.6 [1.1 to 2.2]) was associated with renal cancer. The association with early-adult obesity was stronger among whites than blacks (Test for interaction, P=0.006), while the association with obesity near diagnosis was marginally stronger in women than men (Test for interaction, P=0.08). The strongest association with renal cancer was observed for obese whites both in early adulthood and prior to interview (2.6 [1.5 to 4.4]); this association was not present among blacks. Estimates of the annual excess rate of renal cancer (per 100,000 persons) attributed to both overweight and obesity (BMI > 25 kg/m2) ranged from 9.9 among black men to 5.6 among white women.
Obesity, both early and later in life, is associated with an increased risk of renal cancer. The association with early obesity appears to be stronger among whites than blacks.
Systematic genome-wide reductions of methylated cytosine (5-mC) levels have been observed in colorectal cancer tissue and are suspected to play a role in carcinogenesis, possibly as a consequence of inadequate folate intake. Reduced 5-mC levels in peripheral blood leukocytes have been associated with increased risk of colorectal cancer and adenoma in cross-sectional studies.
To minimize disease- and/or treatment-related effects, we studied leukocyte 5-mC levels in prospectively collected blood specimens of 370 cases and 493 controls who were cancer-free at blood collection from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial., Leukocyte 5-mC level was determined by an HPLC/Tandem Mass Spectrometry method and expressed as the relative amount of methyl- to total cytosine residues, or %5-mC. We estimated the association between colorectal cancer risk and %5-mC categories by computing odds ratios (ORs) and 95% confidence intervals (CIs) through logistic regression modeling.
We observed no dose-dependent association between colorectal cancer and %5-mC categories (lowest tertile vs. highest: OR=1.14, 95% CI=0.80–1.63; P trend=0.51). However, among subjects whose 5-mC levels were at the highest tertile, we observed an inverse association between natural folate intake and colorectal cancer (highest tertile of natural folate vs. lowest: OR=0.35, 95% CI=0.17–0.71; P trend=0.003; P interaction=0.003).
This prospective investigation show no clear association between leukocyte 5-mC level and subsequent colorectal cancer risk, but a suggestive risk modification between 5-mC level and natural folate intake.
Adequate folate status may protect against colorectal carcinogenesis through mechanisms involving adequate DNA methylation in the genome.
5-mC; PLCO; folate; colorectal
H2AFX encodes a histone variant involved in signaling sites of DNA damage and recruiting repair factors. Genetic variants in H2AFX may influence risk of non-Hodgkin lymphoma (NHL), a heterogeneous group of lymphoid tumors that are characterized by chromosomal translocations. We previously reported that rs2509049, a common variant in the promoter of H2AFX, was associated with risk for NHL in the British Columbia population. Here we report results for 13 single nucleotide polymorphisms (SNPs) in 100 Kb surrounding H2AFX in an expanded collection of 568 NHL cases and 547 controls. After correction for multiple testing, significant associations were present for mantle cell lymphoma (p=0.007 for rs604714) and all B-cell lymphomas (p=0.046 for rs2509049). Strong linkage disequilibrium in the 5 Kb upstream of H2AFX limited the ability to determine which specific SNP (rs2509049, rs7759, rs8551, rs643788, rs604714, or rs603826), if any, was responsible. There was a significant interaction between sex and rs2509049 in the all B-cell lymphomas group (p=0.002); a sex-stratified analysis revealed that the association was confined to females (p=0.001). Neither the overall nor the female-specific association with rs2509049 was replicated in any of four independent NHL sample sets. Meta-analysis of all five study populations (3,882 B-cell NHL cases and 3,718 controls) supported a weak association with B-cell lymphoma (OR=0.92, 95% CI=0.86-0.99, p=0.034), although this association was not significant after exclusion of the British Columbia data. Further research into the potential sex-specificity of the H2AFX-NHL association may identify a subset of NHL cases that are influenced by genotype at this locus.
Epidemiological studies have yielded inconsistent associations between vitamin D status and prostate cancer risk, and few studies have evaluated whether the associations vary by disease aggressiveness. We investigated the association between vitamin D status, as determined by serum 25-hydroxy-vitamin D [25(OH)D] level, and risk of prostate cancer in a case–control study nested within the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial.
The study included 749 case patients with incident prostate cancer who were diagnosed 1 to 8 years after blood draw and 781 control subjects who were frequency-matched by age at cohort entry, time since initial screening, and calendar year of cohort entry. All study participants were selected from the trial screening arm (which includes annual standardized prostate cancer screening). Conditional logistic regression was used to estimate odds ratios (ORs) with 95% confidence intervals (CIs) by quintile of 25(OH)D. Statistical tests were two-sided.
No statistically significant trend in overall prostate cancer risk was observed with increasing serum season-standardized 25(OH)D level. However, serum 25(OH)D concentrations greater than the lowest quintile (Q1) associated with increased risk of aggressive (Gleason sum ≥7 or clinical stage III or IV) disease (ORs for Q2 vs Q1 = 1.20, 95% CI = 0.80 to 1.81, for Q3 vs Q1 =1.96, 95% CI = 1.34 to 2.87, for Q4 vs Q1 = 1.61, 95% CI = 1.09 to 2.38, and for Q5 vs Q1 = 1.37, 95% CI = 0.92 to 2.05; Ptrend = .05). The rates of aggressive prostate cancer for increasing quintiles of serum 25(OH)2D were 406, 479, 780, 633, and 544 per 100,000 person-years. In exploratory analyses, these associations with aggressive disease were consistent across subgroups defined by age, family history of prostate cancer, diabetes, body mass index, vigorous physical activity, calcium intake, study center, season of blood collection, and assay batch.
The findings of this large prospective study do not support the hypothesis that vitamin D is associated with decreased risk of prostate cancer; indeed, higher circulating 25(OH)D concentrations may be associated with increased risk of aggressive disease.
25-hydroxy-vitamin D; prostate cancer
We show how to use reports of cancer in family members to discover additional genetic associations or confirm previous findings in genome-wide association (GWA) studies conducted in case-control, cohort, or cross-sectional studies. Our novel family-history-based approach allows economical association studies for multiple cancers, without genotyping of relatives (as required in family studies), follow-up of participants (as required in cohort studies), or oversampling of specific cancer cases, (as required in case-control studies). We empirically evaluate the performance of the proposed family-history-based approach in studying associations with prostate and ovarian cancers, using data from GWA studies previously conducted within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. The family-history-based method may be particularly useful for investigating genetic susceptibility to rare diseases, for which accruing cases may be very difficult, by using disease information from non-genotyped relatives of participants in multiple case-control and cohort studies designed primarily for other purposes.
A recent genome-wide association study of bladder cancer identified the UGT1A gene cluster on chromosome 2q37.1 as a novel susceptibility locus. The UGT1A cluster encodes a family of UDP-glucuronosyltransferases (UGTs), which facilitate cellular detoxification and removal of aromatic amines. Bioactivated forms of aromatic amines found in tobacco smoke and industrial chemicals are the main risk factors for bladder cancer. The association within the UGT1A locus was detected by a single nucleotide polymorphism (SNP) rs11892031. Now, we performed detailed resequencing, imputation and genotyping in this region. We clarified the original genetic association detected by rs11892031 and identified an uncommon SNP rs17863783 that explained and strengthened the association in this region (allele frequency 0.014 in 4035 cases and 0.025 in 5284 controls, OR = 0.55, 95%CI = 0.44–0.69, P = 3.3 × 10−7). Rs17863783 is a synonymous coding variant Val209Val within the functional UGT1A6.1 splicing form, strongly expressed in the liver, kidney and bladder. We found the protective T allele of rs17863783 to be associated with increased mRNA expression of UGT1A6.1 in in-vitro exontrap assays and in human liver tissue samples. We suggest that rs17863783 may protect from bladder cancer by increasing the removal of carcinogens from bladder epithelium by the UGT1A6.1 protein. Our study shows an example of genetic and functional role of an uncommon protective genetic variant in a complex human disease, such as bladder cancer.
In follow-up of a recent genome-wide association study (GWAS) that identified a locus in chromosome 2p21 associated with risk for renal cell carcinoma (RCC), we conducted a fine mapping analysis of a 120 kb region that includes EPAS1. We genotyped 59 tagged common single-nucleotide polymorphisms (SNPs) in 2278 RCC and 3719 controls of European background and observed a novel signal for rs9679290 [P = 5.75 × 10−8, per-allele odds ratio (OR) = 1.27, 95% confidence interval (CI): 1.17–1.39]. Imputation of common SNPs surrounding rs9679290 using HapMap 3 and 1000 Genomes data yielded two additional signals, rs4953346 (P = 4.09 × 10−14) and rs12617313 (P = 7.48 × 10−12), both highly correlated with rs9679290 (r2 > 0.95), but interestingly not correlated with the two SNPs reported in the GWAS: rs11894252 and rs7579899 (r2 < 0.1 with rs9679290). Genotype analysis of rs12617313 confirmed an association with RCC risk (P = 1.72 × 10−9, per-allele OR = 1.28, 95% CI: 1.18–1.39) In conclusion, we report that chromosome 2p21 harbors a complex genetic architecture for common RCC risk variants.
The Agricultural Health Study (AHS) is a prospective study of licensed pesticide applicators (largely farmers) and their spouses in Iowa and North Carolina. We evaluate the impact of occupational pesticide exposure misclassification on relative risks using data from the cohort and the AHS Pesticide Exposure Study (AHS/PES).
We assessed the impact of exposure misclassification on relative risks using the range of correlation coefficients observed between measured post-application urinary levels of 2,4-dichlorophenoxyacetic acid (2,4-D) and chlorpyrifos metabolite and exposure estimates based on an algorithm from 83 AHS pesticide applications.
The correlations between urinary levels of 2,4-D and chlorpyrifos metabolite and estimated exposure intensity scores from the expert-derived algorithm were about 0.4 for 2,4-D (n=64), 0.8 for liquid chlorpyrifos (n=4), and 0.6 for granular chlorpyrifos (n=12). Correlations of urinary levels with individual exposure determinants (e.g., kilograms of active ingredient used, duration of application, or number of acres treated) were lower and ranged from −0.36 to 0.19. These findings indicate that scores from an a priori expert-derived algorithm developed for the AHS were more closely related to measured urinary levels than the several individual exposure determinants evaluated here. Estimates of potential bias in relative risks observed in the AHS based on the correlations from the AHS/PES and the proportion of the AHS cohort exposed to various pesticides indicate that nondifferential misclassification of exposure using the algorithm would bias some estimates toward the null, but less than the misclassification associated with individual exposure determinants.
Based on these correlations and the proportion of the AHS cohort exposed to various pesticides, the potential bias in relative risks from nondifferential exposure misclassification is reduced when exposure estimates are based on an expert algorithm compared to estimates based on separate individual exposure determinants often used in epidemiologic studies. Although correlations between algorithm scores and urinary levels were quite good (i.e., correlations between 0.4 and 0.8), exposure misclassification would still bias relative risk estimates in the AHS towards the null and diminish study power.
Renal cell carcinoma (RCC) is the most lethal urologic cancer. Only two common susceptibility loci for RCC have been confirmed to date. To identify additional RCC common susceptibility loci, we conducted an independent genome-wide association study (GWAS). We analyzed 533 191 single nucleotide polymorphisms (SNPs) for association with RCC in 894 cases and 1516 controls of European descent recruited from MD Anderson Cancer Center in the primary scan, and validated the top 500 SNPs in silico in 3772 cases and 8505 controls of European descent involved in the only published GWAS of RCC. We identified two common variants in linkage disequilibrium, rs718314 and rs1049380 (r2 = 0.64, D ′ = 0.84), in the inositol 1,4,5-triphosphate receptor, type 2 (ITPR2) gene on 12p11.23 as novel susceptibility loci for RCC (P = 8.89 × 10−10 and P = 6.07 × 10−9, respectively, in meta-analysis) with an allelic odds ratio of 1.19 [95% confidence interval (CI): 1.13–1.26] for rs718314 and 1.18 (95% CI: 1.12–1.25) for rs1049380. It has been recently identified that rs718314 in ITPR2 is associated with waist–hip ratio (WHR) phenotype. To our knowledge, this is the first genetic locus associated with both cancer risk and WHR.
We examined the associations between cigarette smoking, alcohol intake, and thyroid cancer risk in a pooled analysis of five prospective studies.
Data from five prospective U.S. studies were standardized and then combined into one aggregate dataset (384,433 men and 361,664 women). Pooled hazard ratios (HR) and 95% confidence intervals (CI) for thyroid cancer were estimated from mutually-adjusted models of cigarette smoking and alcohol intake, which were additionally adjusted for age, sex, education, race, marital status, body mass index, and cohort.
Over follow-up, 1,003 incident thyroid cancer cases (335 men and 668 women) were identified. Compared to never smokers, current smoking was associated with reduced risk of thyroid cancer (HR=0.68, 95% CI:0.55-0.85); this association was slightly stronger among non-drinkers (HR=0.46, 95% CI:0.29-0.74). No reduction in risk was observed for former, compared to never, smokers. Greater smoking intensity, duration, and pack-years were associated with further reductions in risk among former and current smokers. Alcohol intake was also inversely associated with thyroid cancer risk (≥7 drinks/week versus 0, HR=0.72, 95% CI:0.58-0.90, P-trend=0.002). Inverse associations with smoking and alcohol were more pronounced for papillary versus follicular tumors.
The results of this pooled analysis suggest that both cigarette smoking and alcohol consumption are associated with reduced risks of papillary thyroid cancer and, possibly, follicular thyroid cancer.
thyroid neoplasms; cigarette smoking; alcohol intake; prospective study; epidemiology
Serum measurements of cytokines, mediators of various B cell and T cell activities, are important markers of inflammation and immune dysregulation. We assessed the reproducibility of serum cytokine measurements over a five-year period among participants in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO).
Levels of 13 cytokines [interleukin (IL) 1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, interferon-gamma (IFNγ), granulocyte macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor-α (TNFα)] in stored sera from three collections (study baseline, +1 yr, and +5 yr) among 28 randomly selected PLCO participants were measured using a high-sensitivity Luminex xMap-based multiplex panel. Within- and between-subject components of variance were estimated from random effects models and were used to calculate the coefficient of variation (CV) and intraclass correlation coefficient (ICC) for analytes with <30% of samples below the limit of detection (LOD). Spearman correlation coefficients between measurements of the same analyte over time and between analytes were also calculated.
Among the six cytokines with <30% of samples below the LOD, we observed excellent reproducibility for IL-6, IL-7, IL-13, and TNFα (ICC ≥ 0.73), and fair to good reproducibility for IL-8 (ICC = 0.55) and IL-10 (ICC = 0.60). Spearman correlation coefficients comparing paired measurements of each cytokine at baseline and at +5 yr were high (ρ ≥ 0.74) with the exception of IL-10 (ρ = 0.44).
These results suggest that measurements of most of the cytokines evaluated in this study were highly reproducible over a five-year period.
cytokines; inflammation; variability; serum; cancer
Renal cell carcinoma (RCC) incidence is higher among blacks than whites in the United States, and has been associated with the frequency and timing of childbirth among women in some epidemiologic studies. We investigated whether reproductive factors are associated with RCC, overall and by race, within a population-based case-control study.
Between 2002 and 2007, 497 female cases of incident RCC (136 black, 361 white) and 546 female controls (273 black, 273 white) within the Detroit and Chicago metropolitan areas were enrolled. Information on reproductive history and other factors was collected through in-person interviews. Multivariate adjusted odds ratios (OR) and 95% confidence intervals (CI) were computed using unconditional logistic regression.
Reduced RCC risk was observed among women aged ≥30 years at first live birth, relative to an age of <20 years (OR 0.5, 95% CI 0.3–0.9). This association was present among both white (OR 0.4, 95% CI 0.2–0.9) and, though not statistically significant, black women (OR 0.6, 95% CI 0.2–1.8). In analyses restricted to clear cell adenocarcinoma, the most common RCC histologic subtype, the association was particularly strong (OR 0.3, 95% CI 0.2–0.8). We did not observe clear evidence of association with RCC for other reproductive factors.
Our findings further support an association between late maternal age at first birth and reduced RCC risk, and suggest that the association may be particularly strong for clear cell adenocarcinoma.
Renal cell carcinoma; reproductive factors; case-control studies; hysterectomy; parity
Chronic inflammation is etiologically-related to several cancers. We evaluated the performance (ability to detect concentrations above the assay’s lower limit of detection, coefficients-of-variation [CVs], and intraclass correlation coefficients [ICCs]) of 116 inflammation, immune, and metabolic markers across two luminex bead-based commercial kits and three specimen types.
From 100 cancer-free participants in the Prostate, Lung, Colorectal, and Ovarian Cancer Trial, serum, heparin plasma, and EDTA plasma samples were utilized. We measured levels of 67 and 97 markers using Bio-Rad and Millipore kits, respectively. Reproducibility was assessed using 40 blinded duplicates (20 within-batches and 20 across-batches) for each specimen type.
A majority of markers were detectable in >25% of individuals on all specimen types/kits. Of the 67 Bio-Rad markers, 51, 52, and 47 markers in serum, heparin plasma, and EDTA plasma, respectively, had across-batch CVs <20%. Likewise, of 97 Millipore markers, 75, 69, and 78 markers in serum, heparin plasma, and EDTA plasma, respectively, had across-batch CVs <20%. When results were combined across specimen types, 45 Bio-Rad and 71 Millipore markers had acceptable performance (>25% detectability on all 3 specimen types and across-batch CVs <20% on at least 2 of 3 specimen types). Median concentrations and ICCs differed to a small extent across specimen types and to a large extent between Bio-Rad and Millipore.
Inflammation and immune markers can be measured reliably in serum and plasma samples using multiplexed luminex-based methods.
Multiplexed assays can be utilized for epidemiologic investigations into the role of inflammation in cancer etiology.
Although impaired lung function in general has been associated with an increased risk of lung cancer, past studies typically have not attempted to investigate separately the obstructive and restrictive components of respiratory impairment. To deal with this question further, data from a large (n = 176 997) cohort of male Swedish construction workers, for whom spirometry measurements before follow‐up were available, were analysed.
Cancer incidence for 1971–2001 was obtained through linkage with the national cancer registry. Using a modification of the Global Initiative for Chronic Obstructive Lung Disease criteria for chronic obstructive pulmonary disease (COPD), subjects were classified into five categories of lung function: normal, mild COPD, moderate COPD, severe COPD and restrictive lung disease (RLD). Rate ratios (RR) and 95% confidence intervals (CI) for lung cancer across lung function categories were calculated using Poisson regression, adjusted for age and smoking. Other end points (histological types of lung cancer, non‐lung tobacco‐related cancers, other cancers, total mortality) were also investigated.
834 incident cases of lung cancer were identified. Increased rates of lung cancer were observed for both COPD (mild: RR 1.5, 95% CI 1.2 to 1.9; moderate/severe: RR 2.2, 95% CI 1.8 to 2.7) and RLD (RR 2.0, 95% CI 1.6 to 2.5) relative to normal lung function. These associations did not meaningfully change on applying follow‐up lag times of 5, 10 and 15 years after spirometry. When analysed by histological type, associations with both COPD and RLD were stronger for squamous cell carcinoma and small cell carcinoma, and weaker for adenocarcinoma. Both COPD and RLD were associated with increased rates of total mortality.
Obstructive and restrictive impairments in lung function are associated with increased lung cancer risk.
While severe immune dysregulation is an established risk factor for non-Hodgkin lymphoma (NHL), it is unclear whether subclinical immune system function influences lymphomagenesis. To address this question, we conducted a nested case-control study within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial to investigate whether circulating levels of cytokines and other immune markers are associated with future risk of NHL. Selected cytokines [interleukin (IL)-4, IL-6, IL-10, tumor necrosis factor (TNF)-α] and other immune markers [soluble TNF receptor 1 (sTNF-R1), sTNF-R2, C-reactive protein (CRP), sCD27] were measured in prediagnostic serum specimens from 297 incident NHL cases and 297 individually matched controls. Odds ratios (OR) and 95% confidence intervals (CI) relating quartiles of analyte concentration to NHL risk were calculated using conditional logistic regression. Statistically significant associations with increased NHL risk were observed for elevated serum levels of sTNF-R1 (quartile 4 vs. quartile 1: OR 1.7, 95% CI 1.1–2.8; Ptrend=0.02) and sCD27 (OR 5.3, 95% CI 2.9–9.4; Ptrend<0.0001). These associations remained in analyses of cases diagnosed 6+ years following blood collection (sTNF-R1: OR 2.1, 95% CI 1.0–4.0, Ptrend=0.01; sCD27: OR 4.1, 95% CI 1.9–8.5, Ptrend=0.0001). Elevated levels of IL-10, TNF-α and sTNF-R2 were also significantly associated with increased risk of NHL overall; however, these associations weakened with increasing time from blood collection to case diagnosis, and were null for cases diagnosed 6+ years post-collection. Our findings for sTNF-R1 and sCD27, possible markers for inflammatory and B-cell stimulatory states respectively, support a role for subclinical inflammation and chronic B-cell stimulation in lymphomagenesis.
non-Hodgkin lymphoma; cohort studies; serum; cytokines; soluble markers; immune system
Chronic hepatitis C virus (HCV) infection is an established cause of liver cancer, and recent studies have suggested a link with kidney cancer. The aim of this study was to evaluate risk of kidney cancer in relation to HCV infection in a nationwide registry-based study of Swedish residents diagnosed with HCV between 1990 and 2006. A total of 43,000 patients with chronic HCV infection were included, and the mean follow-up time was 9.3 years. Observed kidney cancer incidence and mortality in the cohort were compared with expected values based on the age- and sex-adjusted rates in the general population. Risk of hospitalization for other chronic kidney disease was also evaluated using Cox proportional hazards regression. No association between HCV infection and risk of kidney cancer was observed [standardized incidence ratio with one-year lag = 1.2; 95% confidence interval (CI) 0.8–1.7]. Risk of hospitalization for non-cancer kidney disease was significantly elevated in the HCV cohort, with significantly stronger associations observed among women than among men [hazard ratio = 5.8 (95% CI 4.2–7.9) and 3.9 (95% CI 3.2–4.8) for women and men, respectively]. Results of this study do not support the hypothesis that chronic HCV infection confers an increased risk of kidney cancer. However, we did find an association between HCV infection and chronic kidney disease, particularly among women. Given inconsistent findings in the literature, it is premature to consider HCV infection to be a risk factor for kidney cancer.
chronic hepatitis C virus infection; renal cell carcinoma; kidney cancer; cancer registry; chronic kidney disease
The balance between Th1 and Th2 activity is critical in lymphoid cell development and differentiation. Immune dysfunction underlies lymphomagenesis, so an alteration in the regulation of key Th1/Th2 cytokines may lead to the development of non-Hodgkin lymphoma (NHL). To study the impact of polymorphism in Th1/Th2 cytokines on NHL risk, we analyzed 145 tag single nucleotide polymorphisms (SNPs) in 17 Th1/Th2 cytokine and related genes in three population-based case-control studies (1,946 cases and 1,808 controls). Logistic regression was used to compute odds ratios (OR) for NHL and four major NHL subtypes in relation to tag SNP genotypes and haplotypes. A gene-based analysis adjusting for the number of tag SNPs genotyped in each gene showed significant associations with risk of NHL combined and one or more NHL subtypes for Th1 (IL12A and IL12RB1) and Th2 (IL4, IL10RB, and IL18) genes. The strongest association was for IL12A rs485497, which plays a central role in bridging the cellular and humoral pathways of innate resistance and antigen-specific adaptive immune responses (allele risk OR=1.17; P(trend)=0.00099). This SNP was also associated specifically with risk of follicular lymphoma (allele risk OR=1.26; P(trend)=0.0012). These findings suggest that genetic variation in Th1/Th2 cytokine genes may contribute to lymphomagenesis.
Non-Hodgkin lymphoma; single nucleotide polymorphisms; immunogenetics; case-control study
Multiple myeloma (MM) is a B-cell lymphoid malignancy suspected to be associated with immunologic factors. Given recent findings associating single-nucleotide polymorphisms (SNPs) in innate immunity genes with non-Hodgkin lymphoma, we conducted an investigation of innate immune gene variants using specimens from a population-based case-control study of MM conducted in Connecticut women. Tag SNPs (N=1,461) summarizing common variation in 149 gene regions were genotyped in non-Hispanic Caucasian subjects (103 cases, 475 controls). Odds ratios (OR) and 95% confidence intervals (CI) relating SNP associations with MM were computed using unconditional logistic regression, while the MinP test was used to investigate associations with MM at the gene level. We calculated permutation-adjusted P-values and false discovery rates (FDR) to account for the number of comparisons performed in SNP-level and gene-level tests, respectively. Three genes were associated with MM when controlling for a FDR of ≤10%: SERPINE1 (PMinP<0.0001; FDR=0.02), HGF (PMinP=0.0006; FDR=0.06) and CCR7 (PMinP=0.001; FDR=0.08). Two SNPs demonstrated robust associations: SERPINE1 rs2227667 (P=2.1×10−5, Ppermutation=0.03) and HGF rs17501108 (P=5.0×10−5, Ppermutation=0.07). Our findings suggest that genetic variants in SERPINE1 and HGF, and possibly CCR7, are associated with MM risk, and warrant further investigation in other studies.
epidemiology; myeloma; genetics
Genetic variation in immune-related genes may play a role in the development of non-Hodgkin lymphoma (NHL). To test the hypothesis that innate immunity polymorphisms may be associated with NHL risk, we genotyped 144 tag single nucleotide polymorphisms (tagSNPs) capturing common genetic variation within 12 innate immunity gene regions in three independent population-based case-control studies (1946 cases and 1808 controls). Gene-based analyses found IL1RN to be associated with NHL risk (minP = 0.03); specifically, IL1RN rs2637988 was associated with an increased risk of NHL (per-allele odds ratio = 1.15, 95% confidence interval = 1.05 – 1.27; ptrend = 0.003), which was consistent across study, subtype, and gender. FCGR2A was also associated with a decreased risk of the follicular lymphoma NHL subtype (minP = 0.03). Our findings suggest that genetic variation in IL1RN and FCGR2A may play a role in lymphomagenesis. Given that conflicting results have been reported regarding the association between IL1RN SNPs and NHL risk, a larger number of innate immunity genes with sufficient genomic coverage should be evaluated systematically across many studies.
non-Hodgkin lymphoma; immune; innate immunity; genetic variation; single nucleotide polymorphisms
Organochlorine (OC) insecticides have been regulated as possible human carcinogens primarily on the basis of animal studies. However, the epidemiologic evidence is inconsistent. We investigated the relationship between cancer incidence and OC insecticide use among pesticide applicators enrolled in the Agricultural Health Study, a prospective cohort study of 57,311 licensed applicators in Iowa and North Carolina enrolled between 1993 and 1997. Information on ever use of seven organochlorine insecticides (aldrin, chlordane, DDT, dieldrin, heptachlor, lindane, toxaphene) was collected from a self-administered questionnaire at enrollment. Lifetime exposure-days to OC insecticides were calculated using additional data from a take-home questionnaire completed by 25,291 participants (44% of total). We found no clear evidence of an association between use of OC insecticides and incident cancers (N=1,150) ascertained through December, 2002. When we focused on individual insecticides and structurally similar groups (aldrin and dieldrin; chlordane and heptachlor), significantly increased relative risks of some cancers were observed for use of some chemicals (rectal cancer and chlordane, lung cancer and dieldrin, non-Hodgkin lymphoma (NHL) and lindane, melanoma and toxaphene, leukemia and chlordane / heptachlor). Some significant decreased relative risks were also observed (colon cancer and aldrin; overall cancer and heptachlor). In Conclusion, we did not observe any clear relationship between cancer risk and the use of OC insecticides. Our chemical-specific findings are based on small numbers and multiple comparisons, and should be interpreted with caution; however, some observed associations (lindane and NHL, chlordane/heptachlor and leukemia) are supported by previous evidence.
cancer; pesticides; organochlorines; agriculture; cohort study
We conducted a two-stage genome-wide association study of renal cell carcinoma (RCC) in 3,772 cases and 8,505 controls of European background from 11 studies, and followed up 6 SNPs in three replication studies of 2,198 cases and 4,918 controls. Two loci on the regions of 2p21 and 11q13.3 were associated with RCC susceptibility below genome-wide significance. Two correlated variants (r2 = 0.99 in controls), rs11894252 (P = 1.8×10−8) and rs7579899 (P = 2.3×10−9), map to EPAS1 on 2p21, which encodes hypoxia-inducible- factor-2 alpha, a transcription factor previously implicated in RCC. The second locus, rs7105934, at 11q13, contains no characterized genes (P = 7.8×10−14). In addition, we observed a promising association on 12q24.31 for rs4765623 which maps to the scavenger receptor class B, member 1 (SCARB1) gene (P = 2.6×10−8). Our study reports novel genomic regions associated with RCC risk that may lead to new etiological insights.
The genetic basis of chronic lymphocytic leukemia (CLL) has not been elucidated to date. Although it is the most common hematological malignancy in Caucasians, it is uncommon among Asians. A recent genome-wide scan of CLL in Caucasians identified 6 variants showing strong association. We attempted to replicate these findings in 71 cases of CLL and 1273 controls in Hong Kong Chinese. Three of the 6 variants were significantly associated with CLL. The rs872071 variant (Odds Ratio (95% Confidence Interval) = 1.78 (1.25–2.53), p = 0.0013) in the IRF4 gene region showed the strongest association, similar to that reported in the United Kingdom study. Polymorphisms in SP140 and ACOXL and were also associated with risk of CLL. Further, the mean allele frequencies of the 6 variants were moderately (59%) to extremely (0.5%) lower in the Chinese population compared with Caucasians. These results suggest that variants in three loci may contribute to risk of CLL among Chinese.
genetic polymorphism; chronic lymphocytic leukemia; Chinese
Occupational cohort and case–control studies suggest that trichloroethylene (TCE) exposure may be associated with non-Hodgkin lymphoma (NHL) but findings are not consistent. There is a need for mechanistic studies to evaluate the biologic plausibility of this association. We carried out a cross-sectional molecular epidemiology study of 80 healthy workers that used TCE and 96 comparable unexposed controls in Guangdong, China. Personal exposure measurements were taken over a three-week period before blood collection. Ninety-six percent of workers were exposed to TCE below the current US Occupational Safety and Health Administration Permissible Exposure Limit (100 p.p.m. 8 h time-weighted average), with a mean (SD) of 22.2 (36.0) p.p.m. The total lymphocyte count and each of the major lymphocyte subsets including CD4+ T cells, CD8+ T cells, natural killer (NK) cells and B cells were significantly decreased among the TCE-exposed workers compared with controls (P < 0.05), with evidence of a dose-dependent decline. Further, there was a striking 61% decline in sCD27 plasma level and a 34% decline in sCD30 plasma level among TCE-exposed workers compared with controls. This is the first report that TCE exposure under the current Occupational Safety and Health Administration workplace standard is associated with a decline in all major lymphocyte subsets and sCD27 and sCD30, which play an important role in regulating cellular activity in subsets of T, B and NK cells and are associated with lymphocyte activation. Given that altered immunity is an established risk factor for NHL, these results add to the biologic plausibility that TCE is a possible lymphomagen.
Melanoma rates are rising among young women, possibly due to increasing ultraviolet radiation to previously protected body sites. Therefore, we examined melanoma incidence trends by age, gender, and body site. Descriptive methods were complemented with the age-period-cohort parameters net drift and longitudinal age trend.
Case and population data were obtained from the Surveillance, Epidemiology, and End Results 9 Registries Database (1975-2006). Net drift summarized the average annual percentage change in log-linear rates per year of calendar-time (or year of diagnosis). Longitudinal age trend summarized the average annual percentage change by attained age at diagnosis. Early-and late-onset melanomas have low and high longitudinal age trends, respectively.
There were 105,829 melanomas diagnosed in the SEER 9 Registries. The overall age-adjusted incidence rate (IR)for melanoma was 17.7/100,000 person-years. Age specific IRs were greater among women than men prior to age 40 years. Among women, Irs decreased for all anatomic sites relative to the trunk. The highest net drift occurred in truncal lesions among women (net drift = 3.8%/year of calendar time; 95% CI = 3.5%-4.0%). The lowest longitudinal age trends also were observed for truncal lesions among women (longitudinal age trend = 5.4%/year of attained age; 95% CI = 5.1-5.7).
Though melanoma Irs overall have risen for decades, the combination of high net drift and low longitudinal age trend demonstrate that melanomas are rising preferentially on the trunk among young women.
Future surveillance and analytic studies should consider melanoma effect modification by age, gender, and body site.
Epidemiology; melanoma; skin cancer