The complement system plays an important role in inflammatory and immune responses, and recent evidence has suggested that it may also play a role in lymphomagenesis. We evaluated the association between genetic variation in complement system genes and risk of non-Hodgkin lymphoma (NHL) in a population-based case–control study conducted among women in Connecticut. Tag SNPs in 30 complement genes were genotyped in 432 Caucasian incident cases and 494 frequency-matched controls. A gene-based analysis that adjusted for the number of tag SNPs genotyped in each gene showed a significant association with NHL overall (P = 0.04) as well as with diffuse large B-cell lymphoma (DLBCL) (P = 0.01) for the C1RL gene. A SNP-based analysis showed that a C>T base substitution for C1RL rs3813729 (odds ratio (OR)CT = 0.60, 95% confidence interval (CI) = 0.42–0.87, Ptrend = 0.0062) was associated with a decreased risk of overall NHL, as well as for DLBCL (ORCT = 0.39, 95% CI = 0.20–0.73; Ptrend = 0.0034). Additionally, SNPs (C2 rs497309, A>C and C3 rs344550, G>C) in two complement genes were positively associated with marginal zone lymphoma (MZL) and C1QG was associated with CLL/SLL, but these results were based on a limited number of cases. Our results suggest a potential role of the complement system in susceptibility to NHL; however, our results should be viewed as exploratory and further replication is needed to clarify these preliminary findings.
lymphoma; C1RL; innate immunity; SNP
Asthma has been hypothesized to be associated with lung cancer (LC) risk. We conducted a pooled analysis of 16 studies in the International Lung Cancer Consortium (ILCCO) to quantitatively assess this association and compared the results with 36 previously published studies. In total, information from 585 444 individuals was used. Study-specific measures were combined using random effects models. A meta-regression and subgroup meta-analyses were performed to identify sources of heterogeneity. The overall LC relative risk (RR) associated with asthma was 1.28 [95% confidence intervals (CIs) = 1.16–1.41] but with large heterogeneity (I2 = 73%, P < 0.001) between studies. Among ILCCO studies, an increased risk was found for squamous cell (RR = 1.69, 95%, CI = 1.26–2.26) and for small-cell carcinoma (RR = 1.71, 95% CI = 0.99–2.95) but was weaker for adenocarcinoma (RR = 1.09, 95% CI = 0.88–1.36). The increased LC risk was strongest in the 2 years after asthma diagnosis (RR = 2.13, 95% CI = 1.09–4.17) but subjects diagnosed with asthma over 10 years prior had no or little increased LC risk (RR = 1.10, 95% CI = 0.94–1.30). Because the increased incidence of LC was chiefly observed in small cell and squamous cell lung carcinomas, primarily within 2 years of asthma diagnosis and because the association was weak among never smokers, we conclude that the association may not reflect a causal effect of asthma on the risk of LC.
Cytokines play a critical role in regulating the immune system. In the tumor microenvironment, they influence survival, proliferation, differentiation, and movement of both tumor and stromal cells, and regulate tumor interactions with the extracellular matrix. Given these biologic properties, there is reason to hypothesize that cytokine activity influences the pathogenesis of non-Hodgkin lymphoma (NHL).
We investigated the effect of genetic variation in cytokine genes on NHL prognosis and survival by evaluating genetic variation in individual SNPs as well as the combined effect of multiple deleterious genotypes. Survival information from 496 female incident NHL cases diagnosed during 1996–2000 in Connecticut were abstracted from Connecticut Tumor Registry in 2008. Survival analyses were conducted by comparing Kaplan-Meier curves and hazard ratios (HR) were computed using Cox proportional hazard models adjusting for demographic and tumor characteristics for genes that were suggested by previous studies to be associated with NHL survival.
We found that the variant IL6 genotype is significantly associated (HR=0.42; 95%CI: 0.23–0.77) with a decreased risk of death, as well as relapse and secondary cancer occurrence, among those with NHL. We also found that risk of death, relapse, and secondary cancers varied by specific SNPs for the follicular, DLBCL, and CLL/SLL histologic types. We identified combinations of polymorphisms whose combined deleterious effect significantly alter overall NHL survival and disease-free survival.
Our study provides evidence that the identification of genetic polymorphisms in cytokine genes may help improve the prediction of NHL survival and prognosis.
Non-Hodgkin lymphoma; Cytokines; Single nucleotide polymorphisms; Survival
We conducted a population-based case-control study in Connecticut women to test the hypothesis that genetic variations in Th1 and Th2 cytokine genes may modify the association between blood transfusion and risk of non-Hodgkin lymphoma (NHL). Compared with women without blood transfusion, women with a history of transfusion had an increased risk of NHL if they carried IL10RA (rs9610) GG genotype [odds ratio (OR) = 1.9, 95% confidence interval (CI): 1.1–3.2] or TNF (rs1800629) AG/AA genotypes (OR = 1.6, 95% CI: 0.9–2.7). We also found women with a history of transfusion had a decreased risk of NHL if they carried IL10RA (rs9610) AG/AA genotypes (OR = 0.6, 95% CI: 0.4–0.9) or TNF (rs1800629) GG genotype (OR = 0.7, 95% CI: 0.5–1.0). A similar pattern was also observed for B-cell lymphoma but not for T-cell lymphoma. Statistically significant interactions with blood transfusion were observed for IL10RA (rs9610) (Pforinteraction = 0.003) and TNF (rs1800629) (Pforinteraction = 0.012) for NHL overall and IL10RA (rs9610) (Pforinteraction = 0.001) and TNF (rs1800629) (Pforinteraction = 0.019) for B-cell lymphoma. The results suggest that genetic polymorphisms in TNF and IL10RA genes may modify the association between blood transfusion and NHL risk.
Xuanwei, China, experiences some of the highest rates of lung cancer in China. While lung cancer risk has been linked to the household use of bituminous coal, no study has comprehensively evaluated the risk of lung cancer associated with the mining of this coal in Xuanwei. In Xuanwei, coal is typically extracted from underground mines, without ventilation, and transported to the surface using carts powered by manpower or electricity.
We evaluated the risk of lung cancer and working as a coal miner, in the absence of diesel exhaust exposure, in a population-based case-control study of 260 male lung cancer cases and 260 age-matched male controls with information on occupational histories. Odds ratios (ORs) and 95% confidence intervals (CIs) for working as a coal miner and years of working as a coal miner were calculated by conditional logistic regression, adjusting for potential confounders, such as smoking and household coal use.
We observed an increased risk of lung cancer among coal miners (OR=2.7; 95%CI =1.3–5.6) compared to non-coal miners. Further, a dose-response relationship was observed for the risk of lung cancer and the number of years working as a coal miner (ptrend=0.02), with those working as miners for more than 10 years experiencing an almost 4-fold increased risk (OR=3.8; 95%CI=1.4–10.3) compared to non-coal miners.
These findings suggest that coal mining in Xuanwei may be a risk factor for lung cancer.
Coal mining; lung cancer; occupation; Xuanwei; China
Telomere length plays an important role in chromosomal stability and tumorigenesis, and its measurement in peripheral white blood cell DNA may be a predictor of the development of lung cancer.
Using a new method - monochrome multiplex quantitative PCR -which reduces measurement variability, we compared telomere length relative to standard DNA in white blood cell DNA in 229 incident male lung cancer cases and 229 matched controls within the prospective Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study of male smokers.
Median (10th, 90th percentile) telomere length was 1.13 (0.86, 1.45) in cases and 1.08 (0.85, 1.38) in controls (P = 0.038). Telomere length was inversely associated with pack-years of smoking (Spearman correlation r = −0.16, P = 0.02) among controls. Compared to subjects with shorter telomere length (≤ median), subjects with greater telomere length (> median) had a 1.6-fold (95% CI, 1.06–2.36) increased risk of lung cancer. There was a significant linear relationship between quartiles of telomere length and risk of lung cancer (odds ratios (95% confidence intervals) by quartile: 1.00, 0.98 (0.55–1.73), 1.62 (0.95–2.77), and 1.50 (0.84–2.68); Ptrend = 0.05). In addition, subgroup analysis showed that greater telomere length was associated with increased risk of lung cancer among heavy smokers (> 38 years) (OR, 1.90; 95% CI, 1.00–3.59) but not among light smokers (≤ 38 years) (OR, 1.08; 95% CI, 0.56–2.11) (Pinteraction = 0.01).
Our results suggest that greater telomere length may be associated with higher risk of lung cancer among male smokers.
Telomere length; lung cancer; cohort study
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
Diabetes, obesity, and cigarette smoke, consistent risk factors for pancreatic cancer, are sources of oxidative stress in humans that could cause mitochondrial DNA (mtDNA) damage and increase mtDNA copy number.
To test whether higher mtDNA copy number is associated with increased incident pancreatic cancer, we conducted a nested case-control study in the Alpha-Tocopherol Beta Carotene Cancer Prevention (ATBC) Study cohort of male smokers, aged 50-69 years at baseline. Between 1992 and 2004, 203 incident cases of pancreatic adenocarcinoma occurred (follow-up: 12 years) among participants with whole blood samples used for mtDNA extraction. For these cases and 656 controls, we calculated odds ratios (OR) and 95% confidence intervals using unconditional logistic regression, adjusting for age, smoking, and diabetes history. All statistical tests were two-sided.
Higher mtDNA copy number was significantly associated with increased pancreatic cancer risk (highest vs. lowest mtDNA copy number quintile, OR=1.64, 95%CI=1.01-2.67, continuous OR=1.14, 95% CI 1.06-1.23), particularly for cases diagnosed during the first 7 years of follow-up (OR=2.14,95% CI=1.16-3.96, p-trend=0.01, continuous OR=1.21, 95% CI 1.10-1.33), but not for cases occurring during follow-up of 7 years or greater (OR= 1.14, 95% CI=0.53-2.45, continuous OR=1.05, 95% CI 0.93-1.18).
Our results support the hypothesis that mtDNA copy number is associated with pancreatic cancer and could possibly serve as a biomarker for pancreatic cancer development.
Background: Indoor air pollution (IAP) derived largely from the use of solid fuels for cooking and heating affects about 3 billion people worldwide, resulting in substantial adverse health outcomes, including cancer. Women and children from developing countries are the most exposed populations. A workshop was held in Arlington, Virginia, 9–11 May 2011, to better understand women’s and children’s potential health effects from IAP in developing countries. Workshop participants included international scientists, manufacturers, policy and regulatory officials, community leaders, and advocates who held extensive discussions to help identify future research needs.
Objectives: Our objective was to identify research opportunities regarding IAP and cancer, including research questions that could be incorporated into studies of interventions to reduce IAP exposure. In this commentary, we describe the state of the science in understanding IAP and its associations with cancer and suggest research opportunities for improving our understanding of the issues.
Discussion: Opportunities for research on IAP and cancer include studies of the effect of IAP on cancers other than lung cancer; studies of genetic factors that modify susceptibility; studies to determine whether the effects of IAP are mediated via germline, somatic, and/or epigenetic changes; and studies of the effects of IAP exposure via dermal and/or oral routes.
Conclusions: IAP from indoor coal use increases the risk of lung cancer. Installing chimneys can reduce risk, and some genotypes, including GSTM1-null, can increase risk. Additional research is needed regarding the effects of IAP on other cancers and the effects of different types of solid fuels, oral and dermal routes of IAP exposure, genetic and epigenetic mechanisms, and genetic susceptibility.
cancer; environmental exposures; environmental health risks; epidemiology; household air pollution; indoor air pollution; public health; solid-fuel combustion
The incidence rates of non-Hodgkin lymphoma (NHL) have steadily increased over the last several decades in the United States, and the temporal trends in incidence can only be partially explained by the HIV epidemic. In 1992, an international workshop sponsored by the United States National Cancer Institute concluded that there was an “emerging epidemic” of NHL and emphasized the need to investigate the factors responsible for the increasing incidence of this disease. Over the past two decades, numerous epidemiological studies have examined the risk factors for NHL, particularly for putative environmental and lifestyle risk factors, and international consortia have been established in order to investigate rare exposures and NHL subtype-specific associations. While few consistent risk factors for NHL aside from immunosuppression and certain infectious agents have emerged, suggestive associations with several lifestyle and environmental factors have been reported in epidemiologic studies. Further, increasing evidence has suggested that the effects of these and other exposures may be limited to or stronger for particular NHL subtypes. This paper examines the progress that has been made over the last twenty years in elucidating the etiology of NHL, with a primary emphasis on lifestyle factors and environmental exposures.
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
Immune deficiency is one of the best characterized and strongest known risk factors for non-Hodgkin lymphoma (NHL). We studied the association between single nucleotide polymorphisms (SNPs) in integrin genes that are important components in human innate immunity and the risk of NHL in a population-based case–control study of women in Connecticut, USA. A total of 373 tag SNPs in 33 gene regions were included in the analysis of 448 cases and 525 controls. The ADAM19 rs11466782 SNP was associated with an increased risk of lymphoma (OR, 1.73; 95 % CI, 1.28–2.35; P additive = 0.0004), and the ICAM3 rs2304240 (OR, 0.67; 95 % CI, 0.52–0.86; P additive = 0.002) and the PTGDR rs708486 SNPs (OR, 0.75; 95 % CI, 0.63–0.90; P additive = 0.002) were associated with reduced risk of lymphoma. Two gene regions (ADAM19 (P=0.009) and ICAM3 (P=0.009)) displayed global associations with lymphoma risk at the P<0.01 level. While our results suggest that genetic polymorphisms in integrin genes may play a role in the genesis of lymphoma in women, they should be viewed as exploratory until they are replicated in additional populations.
lymphoma; integrin; innate immunity; single nucleotide polymorphism
Background Emissions from household coal combustion associated with cooking and heating are an important public health issue, particularly in China where hundreds of millions of people are exposed. Although coal emissions are a known human carcinogen, there is still uncertainty about the level of risk for lung and other cancers.
Methods We performed a meta-analysis on 25 case–control studies (10 142 cases and 13 416 controls) to summarize the association between household coal use and lung cancer risk, and to explore the effect modification of this association by geographical location.
Results Using random-effects models, household coal use was found to be associated with lung cancer risk among all studies throughout the world [odds ratio (OR) = 2.15; 95% confidence interval (CI) = 1.61–2.89, Nstudies = 25], and particularly among those studies carried out in mainland China and Taiwan (OR = 2.27; 95% CI = 1.65–3.12, Nstudies = 20). Stratification by regions of mainland China and Taiwan found a variation in effects across the regions, with south/southeastern (OR = 3.27; 95% CI = 1.27–8.42, Nstudies = 3) and southwestern China (OR = 2.98; 95% CI = 1.18–7.53, Nstudies = 3) experiencing the highest risk. The elevated risk associated with coal use throughout Asia was also observed when stratifying studies by gender, smoking status, sample size, design (population vs hospital case–control) and publication language. No significant publication bias was found (pBegg’s = 0.15).
Conclusions Our results provide evidence that although the carcinogenic effect of coal use varies by location, coals from many locations exhibit elevated lung cancer risks.
China; Taiwan; India; indoor air pollution; solid fuels; cooking; heating
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
Evidence suggests that de novo, therapy-related and benzene-induced acute myeloid leukemias (AML) occur via similar cytogenetic and genetic pathways, several of which involve aneuploidy, the loss or gain of chromosomes. Aneuploidy of specific chromosomes has been detected in benzene-related leukemia patients as well as in healthy benzene-exposed workers, suggesting that aneuploidy precedes and may be a potential mechanism underlying benzene-induced leukemia. Here, we analyzed the peripheral blood lymphocytes of 47 exposed workers and 27 unexposed controls using a novel OctoChrome fluorescence in situ hybridization (FISH) technique that simultaneously detects aneuploidy in all 24 chromosomes. Through this chromosome-wide aneuploidy study (CWAS) approach, we found heterogeneity in the monosomy and trisomy rates of the 22 autosomes when plotted against continuous benzene exposure. In addition, statistically significant, chromosome-specific increases in the rates of monosomy [5, 6, 7, 10, 16 and 19] and trisomy [5, 6, 7, 8, 10, 14, 16, 21 and 22] were found to be dose dependently associated with benzene exposure. Furthermore, significantly higher rates of monosomy and trisomy were observed in a priori defined ‘susceptible’ chromosome sets compared with all other chromosomes. Together, these findings confirm that benzene exposure is associated with specific chromosomal aneuploidies in hematopoietic cells, which suggests that such aneuploidies may play roles in benzene-induced leukemogenesis.
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
Using 1996–2000 data among Connecticut women, the authors evaluated whether genetic variation in 4 metabolic genes modifies organic solvent associations with non-Hodgkin lymphoma and 5 major histologic subtypes. Pinteraction values were determined from cross-product terms between dichotomous (ever/never) solvent variables and genotypes at examined loci in unconditional logistic regression models. The false discovery rate method was used to account for multiple comparisons. Overall associations between the chlorinated solvents dichloromethane (odds ratio (OR) = 1.69, 95% confidence interval (CI): 1.06, 2.69), carbon tetrachloride (OR = 2.33, 95% CI: 1.23, 4.40), and methyl chloride (OR = 1.44, 95% CI: 0.94, 2.20) and total non-Hodgkin lymphoma were increased among women TT for rs2070673 in the cytochrome P4502E1 gene, CYP2E1 (dichloromethane: OR = 4.42, 95% CI: 2.03, 9.62; Pinteraction < 0.01; carbon tetrachloride: OR = 5.08, 95% CI: 1.82, 14.15; Pinteraction = 0.04; and methyl chloride: OR = 2.37, 95% CI: 1.24, 4.51; Pinteraction = 0.03). In contrast, no effects of these solvents were observed among TA/AA women. Similar patterns were observed for diffuse large B-cell lymphoma and follicular lymphoma, as well as marginal zone lymphoma for dichloromethane. The weak, nonsignificant overall association between benzene and diffuse large B-cell lymphoma (OR = 1.29, 95% CI: 0.84, 1.98) was increased among women AA for rs2234922 in the microsomal epoxide hydrolase gene, EPHX1 (OR = 1.77, 95% CI: 1.06, 2.97; Pinteraction = 0.06). In contrast, no effect was observed among AG/GG women. Additional studies with larger sample size are needed to replicate these findings.
genetic predisposition to disease; lymphoma, non-Hodgkin; metabolism; occupational exposure; polymorphism, single nucleotide; solvents
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.
In light of the relationship between immune system dysregulation and multiple myeloma (MM) risk, we investigated whether genetic variation in 92 immune function genes among 77 gene regions are associated with MM susceptibility in a population-based case-control study (108 cases and 482 controls) conducted among Caucasian women in Connecticut. Tagging single-nucleotide polymorphisms (SNPs; N=870) were selected using a pairwise linkage-disequilibrium based algorithm. Odds ratios (ORs) and 95% confidence intervals (CIs) for SNP genotypes were estimated using unconditional logistic regression. Tests of association for gene regions were conducted using the minP test. We applied the false discovery rate (FDR) method to the minP test results as a means of controlling for multiple comparisons. The CD4 gene region located on 12p13-q13 (minP=0.0009), had an FDR value < 0.1. In this region, a total of six tag SNPs in two genes (CD4 and LAG3) were significantly associated with MM risk (Ptrend<0.05), with the strongest association observed for the CD4 variant rs11064392 (ORAG/GG=2.53, 95% CI=1.59–4.02). Our findings suggest that genetic variation in CD4 may influence susceptibility to MM. Additional studies are needed to replicate these findings and, more generally, to explore the manner in which genes receptors may influence the pathogenesis of this poorly understood malignancy.
immunoregulatory genes; multiple myeloma; single nucleotide polymorphism; CD4; LAG3
Benzene, a recognized hematotoxicant and carcinogen, can damage the human immune system. We studied the association between single nucleotide polymorphisms (SNPs) in genes involved in innate immunity and benzene hematotoxicity in a cross-sectional study of workers exposed to benzene (250 workers and 140 controls). A total of 1,236 tag SNPs in 149 gene regions of six pathways were included in the analysis. Six gene regions were significant for their association with white blood cell (WBC) counts (MBP, VCAM1, ALOX5, MPO, RAC2, and CRP) based on gene-region (P < 0.05) and SNP analyses (FDR < 0.05). VCAM1 rs3176867, ALOX5 rs7099684, and MPO rs2071409 were the three most significant SNPs. They showed similar effects on WBC subtypes, especially granulocytes, lymphocytes, and monocytes. A 3-SNP block in ALOXE3 (rs7215658, rs9892383, and rs3027208) showed a global association (omnibus P = 0.0008) with WBCs even though the three SNPs were not significant individually. Our study suggests that polymorphisms in innate immunity genes may play a role in benzene-induced hematotoxicity; however, independent replication is necessary.
benzene; hematology; immunity, innate; polymorphism, single nucleotide; toxicity
Mitochondria are eukaryotic organelles responsible for energy production. Mitochondrial DNA (mtDNA) lack introns and protective histones, have limited DNA repair capacity and compensate for damage by increasing the number of mtDNA copies. As a consequence, mitochondria are more susceptible to reactive oxygen species, an important determinant of cancer risk, and it is hypothesized that increased mtDNA copy number may be associated with carcinogenesis. We assessed the association of mtDNA copy number and lung cancer risk in 227 prospectively collected cases and 227 matched controls from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for age at randomization, smoking years and number of cigarettes smoked per day. There was suggestion of a dose-dependent relationship between mtDNA copy number and subsequent risk of lung cancer, with a prominent effect observed in the highest mtDNA copy number quartile [ORs (95% CI) by quartile: 1.0 (reference), 1.3 (0.7–2.5), 1.1 (0.6–2.2) and 2.4 (1.1–5.1); Ptrend = 0.008]. This is the first report, to the best of our knowledge, to suggest that mtDNA copy number may be positively associated with subsequent risk of lung cancer in a prospective cohort study; however, replication is needed in other studies and populations.
Benzene, an established cause of acute myeloid leukemia (AML), may also cause one or more lymphoid malignancies in humans. Previously, we identified genes and pathways associated with exposure to high (> 10 ppm) levels of benzene through transcriptomic analyses of blood cells from a small number of occupationally exposed workers.
The goals of this study were to identify potential biomarkers of benzene exposure and/or early effects and to elucidate mechanisms relevant to risk of hematotoxicity, leukemia, and lymphoid malignancy in occupationally exposed individuals, many of whom were exposed to benzene levels < 1 ppm, the current U.S. occupational standard.
We analyzed global gene expression in the peripheral blood mononuclear cells of 125 workers exposed to benzene levels ranging from < 1 ppm to > 10 ppm. Study design and analysis with a mixed-effects model minimized potential confounding and experimental variability.
We observed highly significant widespread perturbation of gene expression at all exposure levels. The AML pathway was among the pathways most significantly associated with benzene exposure. Immune response pathways were associated with most exposure levels, potentially providing biological plausibility for an association between lymphoma and benzene exposure. We identified a 16-gene expression signature associated with all levels of benzene exposure.
Our findings suggest that chronic benzene exposure, even at levels below the current U.S. occupational standard, perturbs many genes, biological processes, and pathways. These findings expand our understanding of the mechanisms by which benzene may induce hematotoxicity, leukemia, and lymphoma and reveal relevant potential biomarkers associated with a range of exposures.
benzene; biomarker; human; microarray; transcriptomics