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Carcinogenesis Advance Access originally published online on March 16, 2006
Carcinogenesis 2006 27(9):1828-1834; doi:10.1093/carcin/bgl013
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Published by Oxford University Press 2006
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Polymorphisms in oxidative stress genes and risk for non-Hodgkin lymphoma

Sophia S. Wang*, Scott Davis1, James R. Cerhan2, Patricia Hartge, Richard K. Severson3, Wendy Cozen4, Qing Lan, Robert Welch5, Stephen J. Chanock5 and Nathaniel Rothman

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health Rockville, MD, USA
1 Fred Hutchinson Cancer Research Center and the University of Washington Seattle, WA, USA
2 Department of Health Sciences Research, Mayo Clinic College of Medicine Rochester, MN, USA University of Iowa, Iowa City IA, USA
3 Karmanos Cancer Institute and Department of Family Medicine, Wayne State University Detroit, MI, USA
4 University of Southern California Los Angeles, CA, USA
5 Core Genotyping Facility, Advanced Technology Corporation, National Cancer Institute Gaithersburg, MD, USA

*To whom correspondence should be addressed at: Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Boulevard, EPS MSC No. 7234, Bethesda, MD 20892-7234, USA. Tel: +1 301 402 5374; Fax: +1 301 402 0916; Email: wangso{at}mail.nih.gov


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Supplementary Material
 References
 
Evidence supporting the contribution of oxidative stress to key pathways in cancer, such as inflammation and DNA damage, continues to mount. We investigated variations within genes mediating oxidative stress to determine whether they alter risk for non-Hodgkin lymphoma (NHL). Thirteen single nucleotide polymorphisms (SNPs) from 10 oxidative stress genes (AKR1A1, AKR1C1, CYBA, GPX, MPO, NOS2A, NOS3, OGG1, PPARG and SOD2) were genotyped in 1172 NHL cases and 982 population-based controls from a USA multicenter case–control study. For NHL and five subtypes (diffuse large B-cell, follicular, marginal zone, small lymphocytic and T-cell), SNP associations were calculated. Odds ratios (OR) and 95% confidence intervals (CI) were adjusted for sex, age (<45, 45–64, 65+ years), race (white, black, other) and study site. Overall, the oxidative stress pathway was associated significantly with the B-cell NHL subtype, diffuse large B-cell lymphoma (DLBCL) (global P-value = 0.003). Specifically, for nitric oxide synthase (NOS2A Ser608Leu, rs2297518) Leu/Leu homozygotes, there was a 2-fold risk increase for NHL (OR = 2.2, 95% CI = 1.1–4.4) (referent = Ser/Ser and Ser/Leu). This risk increase was consistent by cell lineage (B- and T-cell NHL) and pronounced for the two most common subtypes, diffuse large B-cell (OR = 3.4, 95% CI = 1.5–7.8) and follicular lymphoma (OR = 2.6, 95% CI = 1.0–6.8). In an analysis of manganese superoxide dismutase (SOD2 Val16Ala, rs1799725) Ala/Ala homozygotes, we observed moderately increased risks for B-cell lymphomas (OR = 1.3, 95% CI = 1.0–1.6; referent = Val/Val and Val/Ala) that was consistent across the B-cell subtypes. Genetic variations that result in an increased generation of reactive oxygen species appear to increase risk for NHL and its major subtypes, particularly DLBCL. Independent replication of our findings are warranted and further evaluation of oxidative stress in the context of inflammation, DNA repair and the induction of the NF-{kappa}B pathway may further reveal important clues for lymphomagenesis.

Abbreviations: DLBCL, diffuse large B-cell lymphoma; FPRP, false positive report probabilities; iNOS, inducible nitric oxide synthase; MnSOD, manganese superoxide dismutase; NHL, non-Hodgkin lymphoma; NO, nitric oxide; ROS, reactive oxygen species; SLL, small lymphocytic lymphoma


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 Supplementary Material
 References
 
Identifying exogenous and endogenous sources of inflammation and DNA damage are critically important in understanding cancer etiology. One endogenous source of particular interest is the induction of oxidative stress, defined as a state when levels of free radicals exceed antioxidant defense mechanisms (1). While the generation of free radicals and reactive oxygen species (ROS), including nitric oxide, contributes to a spectrum of normal physiological processes, an excess owing to increased production or inefficient elimination of free radicals or ROS can result in DNA and protein damage (2). The presence of oxidative stress has already been implicated in select inflammatory disorders (e.g. chronic gastritis, pancreatitis, inflammatory bowel disease) and cancers associated with these conditions (1,3). It is therefore hypothesized that genetic variations among enzymes that mediate oxidative stress and the generation of ROS could also modulate cancer risk.

Previous investigations of hematopoietic malignancies have identified three candidate genes with known alterations of functional significance in oxidative stress; namely, the NOS2A gene which encodes inducible nitric oxide synthase (iNOS), the SOD2 gene which encodes the enzyme manganese superoxide dismutase (MnSOD) and the MPO gene which encodes myeloperoxidase (MPO). Briefly, iNOS is an enzyme that can produce high levels of nitric oxide (NO) for prolonged periods of time; although small amounts of NO suppresses tumorigenesis by inducing apoptosis (2), sustained high levels of NO results in chronic inflammation. To date, high levels of iNOS expression as well as NO have been demonstrated in human B-cell non-Hodgkin lymphomas [NHLs; follicular, diffuse large B-cell (DLBCL) and MALT lymphomas] and T-cell leukemias (4–7). The mitochondrial enzyme encoded by the nuclear genome, MnSOD, is a primary antioxidant that protects cells from superoxide radicals by converting ROS into hydrogen peroxide. Recently, MnSOD activity has been shown to modulate apoptosis and suppress tumorigenesis (8), and accordingly, diminished MnSOD activity has been found in lymphoma tumors (4,7). Finally, MPO, primarily expressed in hematopoietic cells, is a critical enzyme for the production of hypochlorous acid, which contributes to antimicrobial activity (9). Reduced MPO expression has previously been associated with increased risk for leukemia and infections (10,11).

Because genetic variations that result in altered enzymatic activity or gene expression for these and other genes important for mediating oxidative stress have been reported previously (12,13), we evaluated a set of common genetic variants with putative functional significance in the risk of NHL in a large population-based case–control study conducted in the USA. To our knowledge, this is the first multigene investigation for main effects of oxidative stress gene polymorphisms in NHL risk. We report results for NHL and for five NHL subtypes [DLBCL, follicular, marginal zone, small lymphocytic (SLL) and T-cell lymphomas].


   Methods
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 Introduction
 Methods
Results
 Discussion
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Study population
The study population has been described in detail previously (14). We included 1321 newly diagnosed NHL cases identified in four Surveillance, Epidemiology and End Results (SEER) registries (Iowa; Detroit, MI; Los Angeles, CA; Seattle, WA) aged 20–74 years between July 1998 and June 2000 without evidence of HIV infection. A total of 1057 population controls were identified by random digit dialing (<65 years) and from Medicare eligibility files (≥65 years). Overall participation rates were 76% in cases and 52% in controls; overall response rates were 59 and 44%, respectively. Written informed consent was obtained from each participant prior to interview, in accordance with US Department of Health and Human Services guidelines. This study was approved by the institutional review boards at the NIH and at each participating SEER site (IA, Seattle, LA and Detroit).

All study participants were asked to provide a venous blood or mouthwash buccal cell sample. We obtained blood samples from 773 cases and 668 controls, and buccal cells from 399 cases and 314 controls. We evaluated the 1172 cases (89%) and 982 controls (93%) for whom biological samples were obtained for genotyping (Table I). Genotype frequencies for individuals who provided blood compared to buccal cells were equivalent (15) and a recent report which included data from our present study found no differences in genotype frequencies by participation status (15).


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  		Table I Characteristics of study participants (n = 2154) who provided blood or buccal cell samples for genotyping

 
Histopathology
Each registry provided NHL pathology and subtype information derived from abstracted reports by the local diagnosing pathologist. All cases were histologically confirmed and coded according to the International Classification of Diseases for Oncology, second edition (16). We evaluated the following NHL histologies: (i) NHL overall, (ii) B-cell lymphomas, (iii) T-cell lymphomas and four B-cell subtypes: (a) DLBCL, (b) follicular, (c) marginal zone and (d) SLL.

Laboratory methods
DNA extraction
DNA was extracted from blood clots or buffy coats (BBI Biotech, Gaithersburg, MD) using Puregene Autopure DNA extraction kits (Gentra Systems, Minneapolis, MN). DNA was extracted from buccal cell samples by phenol–chloroform extraction methods (17).

Genotyping
We selected 13 single nucleotide polymorphisms (SNPs) in 10 oxidative stress genes (Table II) based on evidence of putative functional importance and/or evidence of an association with NHL-associated risk conditions (e.g. autoimmune diseases) in animal or human studies. All genotyping was conducted at the National Cancer Institute Core Genotyping Facility (CGF, Advanced Technology Corporation, Gaithersburg, MD) using the Taqman platform. Sequence data and assay conditions are provided at http://snp500cancer.nci.nih.gov (18). Genotyping results in blood-based DNA samples were analyzed first and further conducted in buccal cell-based DNA when there was sufficient DNA. Successful genotyping was achieved for 96–100% of DNA samples for all SNPs; the completion rates did not differ by blood- or buccal-based DNA and Hardy–Weinberg Equilibrium (HWE) was observed in the control group for each SNP (assessed separately for non-Hispanic Caucasians and Blacks).


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  		Table II Oxidative stress genes and SNPs evaluated in the NCI–SEER multicenter case–control study for NHL

 
Quality control (QC)
Forty replicate samples from each of two blood donors and duplicate samples from 100 study subjects processed in an identical fashion were interspersed for all genotyping assays and blinded from the laboratory. Agreement for QC replicates and duplicates was ≥99% for all assays. For each plate of 368 samples, genotype-specific QC samples were also included and comprised four homozygote wild-type, four heterozygote, four homozygote variant and four DNA negative controls.

Statistical analysis
We calculated odds ratios (OR) as an estimate of the relative risk, and 95% confidence intervals (CI) for each genotype with each NHL histology, using the homozygous wild-type genotype as the referent group. For each histology and genotype, we calculated the P for trend based on the 3-level ordinal variable (0, 1, 2) of homozygote wild-type, heterozygote and homozygote variant. We also evaluated the dominant model with homozygote wild-type was the referent for comparison with heterozygote and homozygote variants, and the recessive model with homozygote wild-type and heterozygote variants combined and used as a referent group for comparison with homozygote variants.

We first conducted stratified analysis by age (<60 and ≥60 years), gender (male/female) and race (non-Hispanic Caucasians and Blacks). Finding no significant differences in the risk estimates by each of these three strata, we pooled the results and adjusted for age (<54, 55–64 and 65+ years), gender (male/female), study site (IA, LA, Seattle and Detroit) and race (white, black and other), as these were all design variables. We note that adjustment by finer age strata (e.g. 10-year strata) provided consistent results but less stable statistical models due to smaller numbers within each stratum. To further assure that our findings were not a result of population stratification (19), we also conducted analyses stratified by study site. Although finding no significant differences by study site, we nevertheless retain it in the model as it was a design variable.

To evaluate the robustness of our risk estimates, we computed the false discovery rate (FDR) (Benjamini–Hochberg adjustment) (20), which reflects the expected ratio of false positive findings to the total number of significant findings. The FDR was computed based on an additive model using the P-trends for each genotype, which allowed the minimal degrees of freedom and thus comparisons (m = 13) for P < 0.05. For each genotype association with a two-sided P-value <0.05, we also calculated the false positive report probabilities (FPRP) (21) using prior probabilities ranging from 0.01 to 0.001 based on gene selection criteria described above. A cut-off of 0.2 was used as the threshold for noteworthiness by the FPRP. We assessed the global significance of the association between oxidative stress SNPs evaluated and NHL with the likelihood ratio {chi}2 statistics comparing the logistic regression models that included all SNPs as the main effects against the null model that included none of the SNPs.


   Results
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 Introduction
 Methods
 Results
Discussion
 Supplementary Material
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In all NHL, we observed a doubling in risk (OR = 2.2, 95% CI = 1.1–4.4, P = 0.03) for individuals homozygous for the non-synonymous SNP in NOS2A (Ser608Leu: Leu/Leu, compared with the referent Ser/Ser and Ser/Leu) (Table III). This risk increase was statistically significant for B-cell lymphomas (OR = 2.2, 95% CI = 1.1–4.5, P = 0.03) and not statistically significantly elevated for T-cell lymphomas (OR = 3.1, 95% CI = 0.6–15.3, P = 0.2). Among B-cell lymphomas, risk for NOS2A Leu/Leu homozygotes was pronounced for the two most common subtypes, diffuse large B-cell (OR = 3.4, 95% CI = 1.5–7.8, P = 0.004) and follicular lymphomas (OR = 2.6, 95% CI = 1.0–6.8, P = 0.05) (Table IV). Except for T-cell lymphomas, no increased risk was observed for NOS2A Leu/Ser heterozygotes, supporting an overall recessive model for NOS2A as described.


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  		Table III Distribution of NOS2A, SOD2, MPO and PPARG genotypes among all NHL, B- and T-cell lymphoma cases and controls

 

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  		Table IV Distribution of NOS2A, SOD2, MPO and PPARG genotypes among DLBCL, follicular, marginal zone and SLL cases and controls

 
There was no association between the SOD2 (Val16Ala) Val/Ala or Ala/Ala genotypes with NHL overall when compared with the common referent group (SOD2 Val/Val) (Table III). However, for SOD2 Ala/Ala homozgyotes (referent: Val/Val and Val/Ala), there was a statistically significant association with B-cell lymphomas (OR = 1.3, 95% CI = 1.0–1.6, P = 0.01) and among the four B-cell subtypes evaluated, risk elevation was statistically significant for SOD2 Ala/Ala homozygotes and diffuse large B-cell lymphoma (OR = 1.3, 95% CI = 1.0–1.8, P = 0.05) (Table IV).

We also evaluated risk for MPO (–463A) GA and AA genotypes (referent = GG); for all NHL, we found a small risk increase (OR = 1.3, 95% CI = 1.1–1.5, P = 0.01) which was observed for both B-cell and T-cell lymphomas although statistically significant only for B-cell lymphomas (Table III). Among B-cell subtypes, the increased risk was also significantly observed in DLBCL (OR = 1.3, 95% CI = 1.0–1.7, P = 0.04). Consistently elevated but not statistically significant risks were observed for follicular (OR = 1.2, 95% CI = 0.9–1.6, P = 0.3), marginal zone (OR = 1.5, 95% CI = 1.0–2.4, P = 0.06) and SLL (OR = 1.2, 95% CI = 0.8–1.7, P = 0.4) (Table IV). All risk increases, however, were driven by the MPO GA heterozygote frequencies; in fact, for NHL and all NHL subtypes, the most robust associations were the increased risks observed among MPO GA heterozygotes. Evaluation of the MPO AA genotype (referent = GG or GA) suggests decreased NHL risk that is consistent across all NHL subtypes evaluated, again driven by frequency differences between cases and controls of the MPO GA heterozygotes (Tables III and IV).

We also report increased risk for follicular lymphoma with the synonymous PPARG His477His polymorphism. When compared with the common homozygote variant (CC), we found a 1.3-fold (95% CI = 0.9–1.9, P = 0.2) increased risk for follicular lymphoma for CT heterozygotes and a 3.0-fold (95% CI-1.2–7.2, P = 0.01) increased risk for TT homozygotes (P-trend = 0.02) (Table IV).

All aforementioned associations were consistent when restricted to non-Hispanic Caucasians. In addition, significant elevations in risk were also observed when investigating joint effects between genes; however, formal tests for interactions were not statistically significant (data not shown). The remaining nine SNPs evaluated in AKR1A1, AKR1C1, CYBA, GPX1, NOS3 and OGG1 were not significantly associated with NHL or any subtype (Online Supplemental Tables 1 and 2). In the overall evaluation of the oxidative stress pathway, we find a global test for significance at P = 0.003 for the B-cell subtype DLBCL. The global test for significance was >0.05 for all NHL and all other subtypes evaluated.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Supplementary Material
 References
 
In our investigation of 13 common SNPs chosen because of putative functional importance drawn from key genes in the oxidative stress pathway, we report that variations in NOS2A, SOD2, MPO and PPARG appear to alter risk for NHL. Although some risk estimates were modest, the overall global test for significance does support further pursuit of the oxidative stress pathway particularly for DLBCL. Confirmation of our results in an independent study is warranted and further identification of critical genes in the oxidative stress pathway associated with NHL and its subtypes could yield important clues to lymphomagenesis as it relates to inflammation and DNA damage.

NOS2A (Ser608Leu) Leu/Leu homozygotes have been reported to confer higher enzymatic activity and iNOS expression (22,23), resulting in increased NO production and inflammation. This is substantiated by TP53 and NOS2 knock-out mice where high levels of anti-inflammatory cytokines that suppress tumorigenesis are found (24). The increased risks we observed for NOS2A homozygotes were notable particularly for their consistency of association; in addition to increased risk for NHL, the association was consistent by cell lineage (B- and T-cell lymphomas) and for the major subtypes DLBCL and follicular lymphoma. Our results are consistent with previous reports that demonstrate iNOS expression in various hematopoietic malignancies, including DLBCL and adult T-cell leukemias (6,25,26). Since the production of endogenous NO results in pro-inflammatory cytokine expression including that from TNF (27), a gene that has previously been associated with increased NHL risk (28), we suggest that an oxidative stress state leading to chronic inflammation could contribute to lymphomagenesis. Although we did not identify further associations with NOS3 polymorphisms, NOS2A produces much higher levels of NO and resulting cytotoxicity (29) compared to the endothelial NOS (eNOS) encoded by NOS3.

Expression of MnSOD plays a critical role in protecting cells from free radicals and oxidative damage (30) but high expression has been found to be deleterious and, in particular, further induced by pro-inflammatory cytokines such as TNF. The functional evidence for the SOD2 (Val16Ala) non-synonymous polymorphism within a signal sequence of the protein coding region has not yet been clarified (31,32). In our data, we find the rare SOD2 Ala/Ala homozygote genotype modestly associated with increased risk for all NHL and its subtypes. This association is consistent with some but not all previous reports for other cancers (33–43). Among hematopoietic cells, total superoxide dismutase activity has been reportedly increased in myelocytic, monocytic and lymphocytic leukemia cells and significantly elevated in leukocytes isolated from patients with malignant lymphomas (44). However, the role of superoxide dismutase activity remains unclear as deficient activity has also been reported in malignant lymphomas (4) and some animal studies have demonstrated reduced MnSOD activity with DNA damage and cancer incidence (13). Further clarification of the role of this gene is therefore required.

MPO is a lysosomal enyme important in neutrophils and monocytes that produces a potent oxidant, hypochlorous acid as well as other ROS, which have antimicrobial activity against a wide range of organisms (9). The unchecked production of hypochlorous acid and metabolism of other exogenous substances (e.g. benzo[a]pyrene) into free radicals, however, contributes to oxidative stress and subsequent inflammation (45). The MPO –463A allele confers a 25-fold decreased MPO expression in vitro (46) and has been found associated with a decreased risk for a number of tumors (33,35) and the high activity allele (G) has been associated with increased risk for acute lymphoblastic leukemia (10). In our data, the GA heterozygote was associated with increased NHL risk that was consistent by cell lineage and for all major NHL subtypes. This puzzling finding drove the observed decreased risk for the AA genotype as shown for other tumors (35,47). Interestingly, this increased risk among GA heterozygotes is similarly found in previously published reports for other tumors (33,35,47). It is plausible that given the dual role of MPO as an antimicrobial agent and as a regulator of inflammation, an independent association might be difficult to tease apart without the presence of the requisite exposure.

Peroxisome proliferator activated receptor-gamma2 (PPAR{gamma}2) has been linked to the production of ROS and PPAR{gamma} agonists have recently been shown to inhibit NF-{kappa}B and its downstream consequences of inflammation (48). It is possible that the synonymous exon 10 PPAR{gamma} polymorphism we evaluated either alters stability of the transcript (49) or it is in linkage disequilibrium with the causal variant. Its modest association with follicular lymphoma in a dose-dependent manner supports a role for oxidative stress in this lymphoma subtype.

To our knowledge, this is the first molecular epidemiologic study to evaluate the association between polymorphisms in oxidative stress genes and risk for NHL. Study strengths include our large sample size for which the associations for each genetic polymorphism could be measured. We believe the accuracy of our genotyping data minimized misclassification, enhancing our ability to detect small effects. Limitations of our study include loss of eligible subjects to death, illness and refusal to participate, limited power to test for interaction and the potential for false positive findings. However, a recent report which included data from our present study found no differences in genotype frequencies by participation status (15). Further, although it is conceivable that individuals participating in the present study are related to survival, preliminary analyses reveal the survival patterns of our cases to be consistent with that of the general population. Only for the NOS2A Leu/Leu genotype which was assigned a prior probability of 0.01 was the FPRP notable with a <20% chance of being a false positive. Adjustments for multiple comparisons by FDR, however, did not yield significant associations; further adjustment which considered all modes of inheritance also did not yield significant associations. Because we did not have adequate power to detect modest associations for rare genotypes and less common subtypes, replication of our findings and analysis of extended haplotypes to identify additional variants of importance are warranted.

In summary, we believe our results support a role for the induction of an oxidative stress state in lymphomagenesis. Our results warrant replication in further studies and detailed haplotype analysis with htSNPs as other polymorphisms may be important as well as the allegedly functional ones we have reported. A detailed evaluation of oxidative stress genes particularly as they relate to the inflammation, the NF-{kappa}B pathway, and DNA damage is justified and large pooled studies that facilitate the evaluation of multiple SNP with NHL subtypes would be optimal in advancing this line of research (28).


   Supplementary Material
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Supplementary Material
References
 
Supplementary material is available at carcinogenesis online.


   Acknowledgments
 
This research was supported by the Intramural Research Program (IRP) of the NIH, National Cancer Institute. Financial support was provided by Public Health Service (PHS) contracts N01-PC-65064, N01-PC-67008, N01-PC-67009, N01-PC-67010 and N02-PC-71105. Funding to pay the Open Access publication charges for this article was provided by NCI IRP.

Conflict of Interest Statement: None declared.


   References
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 Methods
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 References
 

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Received January 10, 2006; revised February 23, 2006; accepted March 7, 2006.


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