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1.  Dietary flavonoid intake and non-Hodgkin lymphoma risk 
The role of dietary factors in non-Hodgkin lymphoma (NHL) risk is not yet well understood. Dietary flavonoids are polyphenolic compounds proposed to be anticarcinogenic. Flavonoids are well-characterized antioxidants and metal chelators, and certain flavonoids exhibit antiproliferative and antiestrogenic effects.
We aimed to evaluate the hypothesis that higher flavonoid intake is associated with lower NHL risk.
During 1998–2000, we identified incident NHL cases aged 20–74 y from 4 US Surveillance, Epidemiology, and End Results cancer registries. Controls without history of NHL were selected by random-digit dialing or from Medicare files and frequency-matched to cases by age, center, race, and sex. Using 3 recently developed US Department of Agriculture nutrient-specific databases, flavonoid intake was estimated from participant responses to a 117-item food-frequency questionnaire (n = 466 cases and 390 controls). NHL risk in relation to flavonoid intake in quartiles was evaluated after adjustment for age, sex, registry, education, NHL family history, and energy intake.
Higher total flavonoid intake was significantly associated with lower risk of NHL (P for trend < 0.01): a 47% lower risk in the highest quartile of intake than in the lowest (95% CI: 31%, 73%). Higher intakes of flavonols, epicatechins, anthocyanidins, and proanthocyanidins were each significantly associated with decreased NHL risk. Similar patterns of risk were observed for the major NHL subtypes—diffuse large B-cell lymphoma (n = 167) and follicular lymphoma (n = 146).
A higher intake of flavonoids, dietary components with several putative anticarcinogenic activities, may be associated with lower NHL risk.
PMCID: PMC3971470  PMID: 18469269
2.  Genetic variation in Th1/Th2 pathway genes and risk of non-Hodgkin lymphoma: A pooled analysis of three population-based case-control studies 
British journal of haematology  2011;153(3):341-350.
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.
PMCID: PMC3075370  PMID: 21418175
Non-Hodgkin lymphoma; single nucleotide polymorphisms; immunogenetics; case-control study
3.  A pooled analysis of three studies evaluating genetic variation in innate immunity genes and non-Hodgkin lymphoma risk 
British Journal of Haematology  2011;152(6):721-726.
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.
PMCID: PMC3253820  PMID: 21250972
non-Hodgkin lymphoma; immune; innate immunity; genetic variation; single nucleotide polymorphisms
To identify occupations and industries associated with non-Hodgkin lymphoma in a large population-based case-control study in the United States.
Cases (n = 1,189) of histologically confirmed malignant NHL ages 20–74 were prospectively identified in four geographic areas covered by the National Cancer Institute SEER Program. Controls (n = 982) were selected from the general population by random digit dialing (< 65 years of age) and from residents listed in Medicare files (65–74 years of age). Odds ratios and 95% confidence intervals for occupations and industries were calculated by unconditional logistic regression analyses, adjusting for age, gender, ethnicity, and study center. Further analyses stratified for gender and histological subtype were also performed.
Risk of NHL was increased for a few occupations and industries. Several white collar occupations, with no obvious hazardous exposures, had elevated risks, including purchasing agents and buyers, religious workers, physical therapists, and information clerks. Occupations with excesses that may have exposures of interest include launderers and ironers, service occupations, food/beverage preparation supervisors, hand packers and packagers, roofing and siding, leather and leather products, transportation by air, nursing and personal care facilities, and specialty outpatient clinics. Significantly decreased risks of NHL were found for a number of occupations and industries including post secondary teachers and chemical and allied products.
The results of this study suggest that several occupations and industries may alter the risk of NHL. Our results support previously reported increased risks among farmers, printers, medical professionals, electronic workers, and leather workers. These findings should be evaluated further in larger studies that have the power to focus on specific exposures and histologic subtypes of NHL.
PMCID: PMC3051169  PMID: 18805886
Non Hodgkin lymphoma; occupation; industry
5.  Genome-wide association study of follicular lymphoma identifies a risk locus at 6p21.32 
Nature genetics  2010;42(8):661-664.
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).
PMCID: PMC2913472  PMID: 20639881
6.  A Case–Control Study of Occupational Exposure to Trichloroethylene and Non-Hodgkin Lymphoma 
Environmental Health Perspectives  2010;119(2):232-238.
Previous epidemiologic findings suggest an association between exposure to trichloroethylene (TCE), a chlorinated solvent primarily used for vapor degreasing of metal parts, and non-Hodgkin lymphoma (NHL).
We investigated the association between occupational TCE exposure and NHL within a population-based case–control study using detailed exposure assessment methods.
Cases (n = 1,189; 76% participation rate) and controls (n = 982; 52% participation rate) provided information on their occupational histories and, for selected occupations, on possible workplace exposure to TCE using job-specific interview modules. An industrial hygienist assessed potential TCE exposure based on this information and a review of the TCE industrial hygiene literature. We computed odds ratios (ORs) and 95% confidence intervals (CIs) relating NHL and different metrics of estimated TCE exposure, categorized using tertiles among exposed controls, with unexposed subjects as the reference group.
We observed associations with NHL for the highest tertiles of estimated average weekly exposure (23 exposed cases; OR = 2.5; 95% CI, 1.1–6.1) and cumulative exposure (24 exposed cases; OR = 2.3; 95% CI, 1.0–5.0) to TCE. Tests for trend with these metrics surpassed or approached statistical significance (p-value for trend = 0.02 and 0.08, respectively); however, we did not observe dose–response relationships across the exposure levels. Overall, neither duration nor intensity of exposure was associated with NHL, although we observed an association with the lowest tertile of exposure duration (OR = 2.1; 95% CI, 1.0–4.7).
Our findings offer additional support for an association between high levels of exposure to TCE and increased risk of NHL. However, we cannot rule out the possibility of confounding from other chlorinated solvents used for vapor degreasing and note that our exposure assessment methods have not been validated.
PMCID: PMC3040611  PMID: 21370516
cancer; non-Hodgkin lymphoma; occupational; solvents; trichloroethylene
7.  Tumor Necrosis Factor (TNF) and Lymphotoxin-α (LTA) Polymorphisms and Risk of Non-Hodgkin Lymphoma in the InterLymph Consortium 
American Journal of Epidemiology  2010;171(3):267-276.
In an International Lymphoma Epidemiology Consortium pooled analysis, polymorphisms in 2 immune-system-related genes, tumor necrosis factor (TNF) and interleukin-10 (IL10), were associated with non-Hodgkin lymphoma (NHL) risk. Here, 8,847 participants were added to previous data (patients diagnosed from 1989 to 2005 in 14 case-control studies; 7,999 cases, 8,452 controls) for testing of polymorphisms in the TNF –308G>A (rs1800629), lymphotoxin-α (LTA) 252A>G (rs909253), IL10 –3575T>A (rs1800890, rs1800896), and nucleotide-binding oligomerization domain containing 2 (NOD2) 3020insC (rs2066847) genes. Odds ratios were estimated for non-Hispanic whites and several ethnic subgroups using 2-sided tests. Consistent with previous findings, odds ratios were increased for “new” participant TNF –308A carriers (NHL: per-allele odds ratio (ORallelic) = 1.10, Ptrend = 0.001; diffuse large B-cell lymphoma (DLBCL): ORallelic = 1.23, Ptrend = 0.004). In the combined population, odds ratios were increased for TNF –308A carriers (NHL: ORallelic = 1.13, Ptrend = 0.0001; DLBCL: ORallelic = 1.25, Ptrend = 3.7 × 10−6; marginal zone lymphoma: ORallelic = 1.35, Ptrend = 0.004) and LTA 252G carriers (DLBCL: ORallelic = 1.12, Ptrend = 0.006; mycosis fungoides: ORallelic = 1.44, Ptrend = 0.015). The LTA 252A>G/TNF –308G>A haplotype containing the LTA/TNF variant alleles was strongly associated with DLBCL (P = 2.9 × 10−8). Results suggested associations between IL10 –3575T>A and DLBCL (Ptrend = 0.02) and IL10 –1082A>G and mantle cell lymphoma (Ptrend = 0.04). These findings strengthen previous results for DLBCL and the LTA 252A>G/TNF –308A locus and provide robust evidence that these TNF/LTA gene variants, or others in linkage disequilibrium, are involved in NHL etiology.
PMCID: PMC2842204  PMID: 20047977
lymphoma; lymphoma, non-Hodgkin; lymphotoxin-alpha; meta-analysis; polymorphism, genetic; polymorphism, single nucleotide; tumor necrosis factor-alpha
8.  Degreasing and risk of non-Hodgkin lymphoma 
To investigate the relationship between selected solvent-related workplace tasks (degreasing, painting, gluing, stripping paint, staining) and risk of non-Hodgkin lymphoma (NHL).
We analyzed occupational data from a large population-based case-control study of NHL conducted in the United States. For participants reporting occupations with possible exposure to organic solvents, job-specific interview modules were administered to elicit in-depth information on solvent-related workplace tasks and other exposure-related factors (225 cases, 189 controls). Unconditional logistic regression models were fit to calculate odds ratios (OR) and 95% confidence intervals (CI) for average frequency, maximal frequency and cumulative number of hours having performed each task. Individuals with jobs rated as unexposed to organic solvents in the workplace (180 cases, 213 controls) were used as a reference group.
We observed an increased risk of NHL among subjects in the highest category of maximal degreasing frequency (>520 hours/year: OR 2.1, 95% CI 0.9-4.9, trend test p=0.02). We found similar associations for the highest levels of average frequency and, among men, cumulative number of hours. Other solvent-related tasks were not associated with NHL.
Findings from this case-control analysis of solvent-related tasks suggest that frequent degreasing work may be associated with an elevated risk of NHL.
PMCID: PMC2995288  PMID: 19017696
non-Hodgkin lymphoma; solvents; case-control studies; degreasing
9.  Polymorphisms in DNA repair genes and risk of non-Hodgkin lymphoma in a pooled analysis of three studies 
British journal of haematology  2010;151(3):239-244.
Elevated incidence of lymphoma has been observed among carriers of rare high-penetrance mutations in DNA repair genes (e.g., Nijmegen breakage syndrome, Ataxia-telangectasia syndrome, etc.). Common gene variants in DNA repair genes may also influence lymphomagenesis.
Study subjects were pooled from three population-based case-control studies of non-Hodgkin lymphoma (NHL) in the US and Australia. A total of 1,946 cases and 1,808 controls were analyzed. A total of 319 tag single nucleotide polymorphisms (SNPs) in 27 DNA repair gene regions were genotyped. Unconditional logistic regression models were used to estimate the relative risk of NHL and NHL subtypes in relation to SNPs. Tail-strength statistics were used to test for the association between DNA repair pathways and NHL or NHL subtypes. The statistical significance of the smallest P-trend within each gene region was estimated by permutation-based resampling methods.
Overall, DNA repair genetic polymorphisms were associated with NHL (P = 0.005). Tests for the double strand break repair (P = 0.02) and nucleotide excision repair (P = 0.04) pathways were also significant. Four gene regions were significantly associated with NHL or NHL subtypes at the 0.05 level: RAD50, BLM, RAD51/FAM82C, and ERCC3/MAP3K2. Specifically, BLM rs441399 (P trend = 0.004) and FAM82C rs2304583 (P trend = 0.001) were associated with follicular lymphoma, and XRCC4 rs13178127 was associated with NHL overall (P trend = 0.006) significantly. In addition, the ERCC3 rs4150506 was associated with reduced risk for marginal zone lymphoma (P trend = 0.002).
These results support the hypothesis that common genetic polymorphisms in human DNA repair genes may modify the risk of NHL.
PMCID: PMC2967772  PMID: 20813000
non-Hodgkin lymphoma; DNA repair; single nucleotide polymorphism; pooled analysis
10.  Vegetables- and antioxidant-related nutrients, genetic susceptibility, and non-Hodgkin lymphoma risk 
Cancer causes & control : CCC  2008;19(5):491-503.
Genetic susceptibility to DNA oxidation, carcinogen metabolism, and altered DNA repair may increase non-Hodgkin lymphoma (NHL) risk, whereas vegetables-and antioxidant-related nutrients may decrease risk. We evaluated the interaction of a priori-defined dietary factors with 28 polymorphisms in these metabolic pathways. Incident cases (n = 1,141) were identified during 1998–2000 from four cancer registries and frequency-matched to population-based controls (n = 949). We estimated diet-gene joint effects using two-phase semi-parametric maximum-likelihood methods, which utilized genotype data from all subjects as well as 371 cases and 311 controls with available diet information. Adjusted odds ratios (95% confidence intervals) were lower among common allele carriers with higher dietary intakes. For the GSTM3 3-base insertion and higher total vegetable intake, the risk was 0.56 (0.35–0.92, p interaction = 0.03); for GSTP1 A114V and higher cruciferous vegetable intake, the risk was 0.52 (0.34–0.81, p interaction = 0.02); for OGG1 S326C and higher daily zinc intake, the risk was 0.71 (0.47–1.08, p interaction = 0.04) and for XRCC3 T241M and higher green leafy vegetable intake, the risk was 0.63 (0.41–0.97, p interaction = 0.03). Calculation of the false positive report probability determined a high likelihood of falsely positive associations. Although most associations have not been examined previously with NHL, our results suggest the examined polymorphisms are not modifiers of the association between vegetable and zinc intakes and NHL risk.
PMCID: PMC2804920  PMID: 18204928
Brassicaceae; Zinc; GST; OGG1; XRCC
11.  Risk of other cancers in individuals with a family history of pancreas cancer 
Journal of gastrointestinal cancer  2007;38(2-4):119-126.
Inherited predisposition to pancreas cancer accounts for approximately 10% of cases. Familial aggregation may be influenced by shared environmental factors and shared genes. We evaluate whether a family history of pancreas cancer is a risk factor for ten specified cancers in first-degree relatives: bladder, breast, colon, head & neck, lung, lymphoma, melanoma, ovary, pancreas and prostate.
Risk factor data and cancer family history were obtained for 1816 first-degree relatives of pancreas cancer case probands (n=247) and 3157 first-degree relatives of control probands (n=420). Unconditional logistic regression models using generalized estimating equations were used to estimate odds ratios (ORs) and 95% confidence intervals of having a first-degree relative a specified cancer.
A family history of pancreas cancer was associated with a doubled risk of lymphoma (OR = 2.83, 95% CI = 1.02–7.86) and ovarian cancer (OR = 2.25, 95% CI = 0.77–6.60) among relatives after adjustment. Relatives with a family history of early-onset pancreas cancer in a proband had a 7-fold increased risk of lymphoma (OR = 7.31, 95% CI = 1.45 – 36.7). Relatives who ever smoked and had a family history of pancreas cancer had a 5-fold increased risk of ovarian cancer (OR = 4.89, 95% CI = 1.16–20.6).
Family history assessment of cancer risk should include all cancers. Assessment of other known and suspected risk factors in relatives will improve risk evaluation. As screening and surveillance methods are developed, identifying those at highest risk is crucial for a successful screening program.
PMCID: PMC2719298  PMID: 19089664
pancreas cancer; lymphoma; ovarian cancer; family history of pancreas cancer; smoking; young age at cancer diagnosis; genetic risk
12.  Asthma history, occupational exposure to pesticides and the risk of non-Hodgkin’s lymphoma 
We previously reported that, although asthma did not increase the risk of non-Hodgkin’s lymphoma (NHL), the risk from pesticide exposures was higher among asthmatics than that among nonasthmatics. To further evaluate this finding, we analyzed data from a population-based case–control study of NHL conducted in Iowa, Detroit, Los Angeles and Seattle. Cases (n = 668) diagnosed with NHL from 1998 to 2000 and controls (n = 543) randomly selected from the same geographical areas as that of the cases were included in this analysis. Odds ratios (OR) for the risk of NHL from potential occupational exposure to pesticides tended to be higher among asthmatics (OR = 1.7; 95% CI 0.3–9.1) when compared with that among nonasthmatics (OR = 0.9; 95% CI 0.6–1.5). The risks of NHL associated with pesticide exposure were also higher among asthmatics who had history of hospitalization (OR = 2.1; 95% CI 0.2–29.0) or daily medication for asthma (OR = infinite) than those among asthmatics who did not have such histories. Our results support the previous finding that the risk of NHL from pesticide exposure may be greater among asthmatics.
PMCID: PMC1578637  PMID: 16395708
asthma; non-Hodgkin’s lymphoma; pesticide exposure
13.  Genetic variation in N-acetyltransferase 1 (NAT1) and 2 (NAT2) and risk of non-Hodgkin lymphoma 
Pharmacogenetics and genomics  2006;16(8):537-545.
Animal studies suggest that lymphomagenesis can be induced by exposure to carcinogenic aromatic and heterocyclic amines found in diet, cigarette smoke, and the environment, but human epidemiologic investigations of these exogenous exposures have yielded conflicting results. As part of our evaluation of the role of aromatic and heterocyclic amines, which are metabolized by N-acetyltransferase (NAT) enzymes, in the etiology of non-Hodgkin lymphoma (NHL), we examined NHL risk in relation to genetic variation in NAT1 and NAT2 and exposure to cigarette smoke and dietary heterocyclic amines and mutagens.
We genotyped ten common single nucleotide polymorphisms (SNPs) in NAT1 and NAT2 among 1136 cases and 922 controls from a population-based case–control study in four geographic areas of the US. Relative risk of NHL for NAT1 and NAT2 genotypes, NAT2 acetylation phenotype, and exposure to cigarette smoke and dietary heterocyclic amines and mutagens was estimated using odds ratios (ORs) and 95% confidence intervals (CIs) derived from unconditional logistic regression models.
We observed increased risk of NHL among individuals with the NAT1*10/*10 genotype compared with individuals with other NAT1 genotypes (OR=1.60, 95% CI 1.04–2.46, p=0.03). We also observed increased NHL risk in a dose-dependent model among NAT2 intermediate- and rapid-acetylators in comparison with slow-acetylators, although only the trend was statistically significant (intermediate: OR=1.18, 95% CI 0.97–1.44, p=0.1; rapid: OR=1.43, 95% CI 0.97–2.14, p=0.07; p for linear trend=0.03). Compared with nonsmokers, NHL risk estimates for current cigarette smoking were increased only among NAT2 intermediate/rapid-acetylators (OR=2.44, 95% CI 1.15–5.20, p=0.02).
Our data provide evidence that NAT1 and NAT2 genotypes are associated with NHL risk and support a contributory role for carcinogenic aromatic and/or heterocyclic amines in the multi-factorial etiology of NHL.
PMCID: PMC1986787  PMID: 16847422
lymphoma, non-Hodgkin; N-acetyltransferase 1; N-acetyltransferase 2; genetic variation; polymorphism, single nucleotide

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