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
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.
To test the hypothesis that bladder cancer is a heterogeneous disease.
Patients and Methods
We examined the temporal trends of bladder cancer by histological subtype and by disease stage and grade using the National Cancer Institute's Surveillance, Epidemiology, and End Results data collected in 1973–2007.
The age-adjusted incidence rates of bladder cancer showed a slight decrease from 1973 to 2007 (annual percentage change [APC] = −0.4, P < 0.05).
Although the age-adjusted incidence rates of non-papillary transitional cell carcinoma decreased by about 53% from 7.9 per 100 000 in 1973 to 3.7 per 100 000 in 2007 (APC = −2.2, P < 0.05), the age-adjusted incidence rates of papillary transitional cell carcinoma increased by about 56% from 6.8 per 100 000 in 1973 to 10.6 per 100 000 in 2007 (APC=0.5, P < 0.05).
Among other rare histological subtypes, except for small cell carcinoma which showed a slightly rising trend, squamous cell carcinoma, adenocarcinoma and others all presented a decreasing trend.
Similar patterns were found for different stages (localized, regional and distant), but a dramatic increasing trend of grade IV was found between 1998 and 2007 when a corresponding decreasing trend was shown for grades I, II and III.
The results support the hypothesis that bladder cancer is a heterogeneous disease and taking disease heterogeneity into consideration in future epidemiological studies is essential.
bladder cancer; transitional cell carcinoma; papillary transitional cell carcinoma; non-papillary transitional cell carcinoma; incidence; mortality
Tumor-associated autoantibodies (AAbs) have been described in patients with lung cancer, and the EarlyCDT®-Lung test that measures such AAbs is available as an aid for the early detection of lung cancer in high-risk populations. Improvements in specificity would improve its cost-effectiveness, as well as reduce anxiety associated with false positive tests. Samples from 235 patients with newly diagnosed lung cancer and matched controls were measured for the presence of AAbs to a panel of six (p53, NY-ESO-1, CAGE, GBU4-5, Annexin I, and SOX2) or seven (p53, NY-ESO-1, CAGE, GBU4-5, SOX2, HuD, and MAGE A4) antigens. Data were assessed in relation to cancer type and stage. The sensitivity and specificity of these two panels were also compared in two prospective consecutive series of 776 and 836 individuals at an increased risk of developing lung cancer. The six-AAb panel gave a sensitivity of 39 % with a specificity of 89 %, while the seven-AAb panel gave a sensitivity of 41 % with a specificity of 91 % which, once adjusted for occult cancers in the population, resulted in a specificity of 93 %. Analysis of these AAb assays in the at-risk population confirmed that the seven-AAb panel resulted in a significant increase in the specificity of the test from 82 to 90 %, with no significant change in sensitivity. The change from a six- to a seven-AAb assay can improve the specificity of the test and would result in a PPV of 1 in 8 and an overall accuracy of 92 %.
Autoantibodies; Lung cancer; Lung cancer diagnosis
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
To investigate the potential association between domestic exposure to light at night (LAN) and the risk of human breast cancer.
A case–control study of female breast cancer was conducted in Connecticut. A total of 363 incident breast cancer cases and 356 age frequency-matched controls were interviewed using a standardized, structured questionnaire to obtain information on sleeping patterns and bedroom light environment. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by unconditional multivariate logistic regression.
A non-significantly increased risk of breast cancer was observed among postmenopausal women for those keeping lights on while sleeping (OR = 1.4, 95% CI 0.7, 2.7), those who reported mainly sleeping in the daytime (OR = 1.4, 95% CI 0.5, 4.3), and those not drawing the curtains/window shades while sleeping at night (OR = 1.2, 95% CI 0.8, 1.9).
The results from this study suggest a potential increased risk of breast cancer associated with domestic exposure to LAN. Further studies with larger sample size are needed to confirm the results.
Light at night; Breast cancer; Case–control study
Epidemiological studies have shown that moderate alcohol drinkers have a lower death rate for all causes. Alcohol drinking has also been associated with reduced risk of non-Hodgkin lymphoma (NHL). Here, we examined the role of alcohol consumption on NHL survival by type of alcohol consumed and NHL subtype.
A cohort of 575 female NHL incident cases diagnosed during 1996–2000 in Connecticut was followed-up for a median of 7.75 years. Demographic, clinical, and lifestyle information was collected at diagnosis. Survival analyses were conducted with Kaplan-Meier methods, and hazard ratios (HR) were estimated from Cox Proportional Hazards models.
Compared to never drinkers, wine drinkers experienced better overall survival (75% vs. 69% five-year survival rates, p-value for log-rank test=0.030) and better disease free survival (70% vs. 67% five-year disease-free survival rates, p-value for log-rank test=0.049). Analysis by NHL subtype shows that the favorable effect of wine consumption was mainly seen for patients diagnosed with diffuse large B-cell lymphoma (DLBCL) (wine drinkers for more than 25 years vs. never drinkers: HR=0.36, 95% CI 0.14–0.94 for overall survival; HR=0.38, 95% CI 0.16–0.94 for disease-free survival), and the adverse effect of liquor consumption was also observed among DLBCL patients (liquor drinkers vs. never drinkers: HR=2.49, 95% CI 1.26–4.93 for disease-free survival).
Our results suggest a moderate relationship between pre-diagnostic alcohol consumption and NHL survival, particularly for DLBCL. The results need to be replicated in larger studies.
Implications for cancer survivors
Pre-diagnostic behaviors might impact the prognosis and survival of NHL patients.
Alcohol; Wine; Liquor; Non-Hodgkin lymphoma; Prognosis; Survival
The incidence of non-Hodgkin lymphoma has substantially increased during the past several decades, and although established risk factors such as immunodeficiency and viral infection may be responsible for a portion of the cases, the vast majority of the NHL cases remain unexplained. Dietary nitrate and nitrite intake are exposures of particular interest for non-Hodgkin lymphoma risk as they have been shown to cause lymphomas in animal studies and there is growing evidence of adverse impact in the epidemiological literature. We investigated NHL risk in general and by subtype in relation to dietary nitrate and nitrite intake in a population-based case-control study of 1,304 women in Connecticut. Nitrate and nitrite intake was assessed using a 120-item food frequency questionnaire. We found no association between risk of NHL and dietary nitrate and a slightly increased risk of NHL for higher dietary nitrite intake (OR = 1.37; 95% CI: 1.04–1.79). The risk was significantly increased for diffuse large B-cell lymphoma (OR = 1.61; 95% CI: 1.08–2.42), follicular lymphoma (OR = 1.61; 95% CI: 1.02–2.54), and T-cell lymphoma (OR = 2.38; 95% CI: 1.12–5.06). Animal products containing nitrite appear to be driving the risk for DLBC lymphoma and follicular lymphoma, whereas the risk for T-cell lymphoma is being driven by plant products. Our results confirm a previous finding for nitrite intake and highlight the importance of evaluating NHL risk by histologic type. We conclude that these results should be replicated in a larger study with data on water consumption as well as diet.
Non-Hodgkin lymphoma; nitrate and nitrite; diet
Non-Hodgkin lymphoma (NHL) represents a diverse group of hematological
malignancies, of which follicular lymphoma (FL) is a prevalent subtype. A
previous genome-wide association study has established a marker, rs10484561 in
the human leukocyte antigen (HLA) class II region on 6p21.32 associated with
increased FL risk. Here, in a three-stage genome-wide association study,
starting with a genome-wide scan of 379 FL cases and 791 controls followed by
validation in 1,049 cases and 5,790 controls, we identified a second independent
FL–associated locus on 6p21.32, rs2647012
(ORcombined = 0.64,
Pcombined = 2×10−21)
located 962 bp away from rs10484561 (r2<0.1 in controls). After
mutual adjustment, the associations at the two SNPs remained genome-wide
significant (rs2647012:ORadjusted = 0.70,
Padjusted = 4×10−12;
rs10484561:ORadjusted = 1.64,
Padjusted = 5×10−15).
Haplotype and coalescence analyses indicated that rs2647012 arose on an
evolutionarily distinct haplotype from that of rs10484561 and tags a novel
allele with an opposite (protective) effect on FL risk. Moreover, in a follow-up
analysis of the top 6 FL–associated SNPs in 4,449 cases of other NHL
subtypes, rs10484561 was associated with risk of diffuse large B-cell lymphoma
(ORcombined = 1.36,
Pcombined = 1.4×10−7).
Our results reveal the presence of allelic heterogeneity within the HLA class II
region influencing FL susceptibility and indicate a possible shared genetic
etiology with diffuse large B-cell lymphoma. These findings suggest that the HLA
class II region plays a complex yet important role in NHL.
Earlier studies have established a marker rs10484561, in the HLA class II region
on 6p21.32, associated with increased follicular lymphoma (FL) risk. Here, in a
three-stage genome-wide association study of 1,428 FL cases and 6,581 controls,
we identified a second independent FL–associated marker on 6p21.32,
rs2647012, located 962 bp away from rs10484561. The associations at two SNPs
remained genome-wide significant after mutual adjustment. Haplotype and
coalescence analyses indicated that rs2647012 arose on an evolutionarily
distinct lineage from that of rs10484561 and tags a novel allele with an
opposite, protective effect on FL risk. Moreover, in an analysis of the top 6
FL–associated SNPs in 4,449 cases of other NHL subtypes, rs10484561 was
associated with risk of diffuse large B-cell lymphoma. Our results reveal the
presence of allelic heterogeneity at 6p21.32 in FL risk and suggest a shared
genetic etiology with the common diffuse large B-cell lymphoma subtype.
To identify susceptibility loci for non-Hodgkin lymphoma (NHL) subtypes, we conducted a three-stage genome-wide association study. We identified two variants associated with follicular lymphoma (FL) in 1,465 FL cases/6,958 controls at 6p21.32 (rs10484561, rs7755224, r2=1.0; combined p-values=1.12×10-29, 2.00×10-19), providing further support that MHC genetic variation influences FL susceptibility. Confirmatory evidence of a previously reported association was also found between chronic lymphocytic leukemia/small lymphocytic lymphoma and rs735665 (combined p-value=4.24×10-9).
Motivation: Although NHL (non-Hodgkin's lymphoma) is the fifth leading cause of cancer incidence and mortality in the USA, it remains poorly understood and is largely incurable. Biomedical studies have shown that genomic variations, measured with SNPs (single nucleotide polymorphisms) in genes, may have independent predictive power for disease-free survival in NHL patients beyond clinical measurements.
Results: We apply the CTGDR (clustering threshold gradient directed regularization) method to genetic association studies using SNPs, analyze data from an association study of NHL and identify prognosis signatures to diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL), the two most common subtypes of NHL. With the CTGDR method, we are able to account for the joint effects of multiple genes/SNPs, whereas most existing studies are single-marker based. In addition, we are able to account for the ‘gene and SNP-within-gene’ hierarchical structure and identify not only predictive genes but also predictive SNPs within identified genes. In contrast, existing studies are limited to either gene or SNP identification, but not both. We propose using resampling methods to evaluate the predictive power and reproducibility of identified genes and SNPs. Simulation study and data analysis suggest satisfactory performance of the CTGDR method.
Supplementary information: Supplementary data are available at Bioinformatics online.
We conducted a population-based case–control study in Connecticut women to test the hypothesis that genetic variations in Th1 and Th2 cytokine genes modify the relationship between hormone replacement therapy (HRT) and risk of non-Hodgkin lymphoma (NHL). Compared to women without a history of HRT use, women with a history of HRT use had a significantly decreased risk of NHL if they carried IFNGR2 (rs1059293) CT/TT genotypes (OR = 0.5, 95%CI: 0.3–0.9), IL13 (rs20541) GG genotype (OR = 0.6, 95%CI: 0.4–0.9), and IL13 (rs1295686) CC genotype (OR = 0.6, 95%CI: 0.4–0.8), but not among women who carried IFNGR2 CC, IL13 AG/AA, and IL13CT/TT genotypes. A similar pattern was also observed for B-cell lymphoma but not for T-cell lymphoma. A statistically significant interaction was observed for IFNGR2 (rs1059293 Pfor interaction = 0.024), IL13(rs20541 Pfor interaction = 0.005), IL13 (rs1295686 Pfor interaction = 0.008), and IL15RA (rs2296135 Pfor interaction = 0.049) for NHL overall; IL13 (rs20541 Pfor interaction = 0.0009), IL13(rs1295686 Pfor interaction = 0.0002), and IL15RA (rs2296135 Pfor interaction = 0.041) for B-cell lymphoma. The results suggest that common genetic variation in Th1/Th2 pathway genes may modify the association between HRT and NHL risk.
non-Hodgkin lymphoma; HRT; genetic polymorphisms; Th1/Th2 cytokines
Cigarette smoke contains many carcinogens that are metabolically activated through xenobiotic metabolism by phase I and II enzymes, including N-acetyltransferases 1 and 2 (NAT1 and NAT2). We investigated non-Hodgkin lymphoma (NHL) risk in general and by subtype in relation to NAT1 and NAT2 genotypes and cigarette smoking in a population-based case-control study in Connecticut. We found a 2-fold increased risk of T-cell lymphoma among those possessing the NAT1*10 haplotype compared to those with other NAT1 haplotypes; including an OR of 2.2 (95%CI: 1.1–4.5) for those heterozygous for NAT1*10 and an OR of 2.0 (95% CI: 1.0–2.4) for those heterozygous or homozygous for NAT1*10 genotypes. Rapid acetylator NAT2 phenotype increased the risk of both T-cell lymphoma (OR=3.2; 95% CI: 1.1–9.5) and marginal zone lymphoma (OR=3.0; 95% CI: 1.0–8.7). When NAT1 and NAT2 genotypes were stratified by smoking status, an increased risk of NHL overall was observed in ever (OR=1.5; 95% CI: 1.1–2.1) and current (OR=1.7; 95% CI: 1.2–2.4) smokers without the NAT1*10 haplotype. No association between history of cigarette smoking and risk of NHL overall was observed with NAT1*10 haplotype or NAT2 genotype.
non-Hodgkin lymphoma; NAT1; NAT2; smoking; single nucleotide polymorphisms
A population-based case-control study involving 601 incident cases of non-Hodgkin lymphoma (NHL) and 717 controls was conducted in 1996–2000 among Connecticut women to examine associations with exposure to organic solvents. A job-exposure matrix was used to assess occupational exposures. Increased risk of NHL was associated with occupational exposure to chlorinated solvents (odds ratio (OR) = 1.4, 95% confidence interval (CI): 1.1, 1.8) and carbon tetrachloride (OR = 2.3, 95% CI: 1.3, 4.0). Those ever exposed to any organic solvent in work settings had a borderline increased risk of NHL (OR = 1.3, 95% CI: 1.0, 1.6); moreover, a significantly increased risk was observed for those with average probability of exposure to any organic solvent at medium-high level (OR = 1.5, 95% CI: 1.1, 1.9). A borderline increased risk was also found for ever exposure to formaldehyde (OR = 1.3, 95% CI: 1.0, 1.7) in work settings. Risk of NHL increased with increasing average intensity (P = 0.01), average probability (P < 0.01), cumulative intensity (P = 0.01), and cumulative probability (P < 0.01) level of organic solvent and with average probability level (P = 0.02) and cumulative intensity level of chlorinated solvent (P = 0.02). Analyses by NHL subtype showed a risk pattern for diffuse large B-cell lymphoma similar to that for overall NHL, with stronger evidence of an association with benzene exposure. Results suggest an increased risk of NHL associated with occupational exposure to organic solvents for women.
case-control studies; lymphoma, non-Hodgkin; risk factors; solvents
An increased incidence of thyroid cancer has been reported in many parts of the world including the United States during the past several decades. Recently emerging evidence has demonstrated that polyhalogenated aromatic hydrocarbons (PHAHs), particularly polybrominated diphenyl ethers (PBDEs), alter thyroid hormone homeostasis and cause thyroid dysfunction. However, few studies have been conducted to test whether exposure to PBDEs and other PHAHs increases the risk of thyroid cancer. Here, we hypothesize that elevated exposure to PHAHs, particularly PBDEs, increases the risk of thyroid cancer and may explain part of the increase in incidence of thyroid cancer during the past several decades. In addition, genetic and epigenetic variations in metabolic pathway genes may alter the expression and function of metabolic enzymes which are involved in the metabolism of endogenous thyroid hormones and the detoxification of PBDEs and other PHAHs. Such variation may result in different individual susceptibilities to PBDEs and other PHAHs and the subsequent development of thyroid cancer. The investigation of this hypothesis will lead to an improved understanding of the role of PBDEs and other PHAHs in thyroid tumorigenesis and may provide a real means to prevent this deadly disease.
Circadian disruption is theorized to cause immune dysregulation, which is the only established risk factor for non-Hodgkin’s lymphoma (NHL). Genes responsible for circadian rhythm are also involved in cancer-related biological pathways as potential tumor suppressors. However, no previous studies have examined associations between circadian genes and NHL risk. In this population-based case control study (n = 455 cases; 527 controls), we examined the only identified nonsynonymous polymorphism (Ala394Thr; rs2305160) in the largest circadian gene, neuronal PAS domain protein 2 (NPAS2), in order to examine its impact on NHL risk. Our results demonstrate a robust association of the variant Thr genotypes (Ala/Thr and Thr/Thr) with reduced risk of NHL (OR = 0.66, 95% CI: 0.51–0.85, p = 0.001), especially B-cell lymphoma (OR = 0.61, 95% CI: 0.47–0.80, p ≤ 0.0001). These findings provide the first molecular epidemiologic evidence supporting a role of circadian genes in lymphomagenesis, which suggests that genetic variations in circadian genes might be a novel panel of promising biomarkers for NHL and warrants further investigation.
NPAS2; NHL; circadian gene
The ancient adaptation of a 24-hour circadian clock has profound effect on our daily biochemical, physiologic, and behavioral processes, including the monitoring of sex hormone levels. Although the disruption of the circadian cycle has been implicated in the etiology of hormone-related female breast cancer, few studies have been undertaken to determine if a link exists in the development of the most common cancer type among men whose etiology remains largely unknown: hormone-related prostate cancer. Here, we hypothesize that both altered-lighted environments and genetic variations in genes responsible for maintaining circadian rhythms may result in deregulation of clock-associated biological processes, such as androgen expression, and consequently influence an individual’s risk of prostate cancer. There is also a potential for the interaction of genetic variants and exposures, such as evening shift work. Confirmation of this hypothesis will add to our understanding of the role of the circadian clock in prostate tumorigenesis and further facilitate the development of novel risk and prognostic biomarkers for prostate cancer.
Objective To estimate the burden of melanoma resulting from sunbed use in western Europe.
Design Systematic review and meta-analysis.
Data sources PubMed, ISI Web of Science (Science Citation Index Expanded), Embase, Pascal, Cochrane Library, LILACS, and MedCarib, along with published surveys reporting prevalence of sunbed use at national level in Europe.
Study selection Observational studies reporting a measure of risk for skin cancer (cutaneous melanoma, squamous cell carcinoma, basal cell carcinoma) associated with ever use of sunbeds.
Results Based on 27 studies ever use of sunbeds was associated with a summary relative risk of 1.20 (95% confidence interval 1.08 to 1.34). Publication bias was not evident. Restricting the analysis to cohorts and population based studies, the summary relative risk was 1.25 (1.09 to 1.43). Calculations for dose-response showed a 1.8% (95% confidence interval 0% to 3.8%) increase in risk of melanoma for each additional session of sunbed use per year. Based on 13 informative studies, first use of sunbeds before age 35 years was associated with a summary relative risk of 1.87 (1.41 to 2.48), with no indication of heterogeneity between studies. By using prevalence data from surveys and data from GLOBOCAN 2008, in 2008 in the 15 original member countries of the European Community plus three countries that were members of the European Free Trade Association, an estimated 3438 cases of melanoma could be attributable to sunbed use, most (n=2341) occurring among women.
Conclusions Sunbed use is associated with a significant increase in risk of melanoma. This risk increases with number of sunbed sessions and with initial usage at a young age (<35 years). The cancerous damage associated with sunbed use is substantial and could be avoided by strict regulations.