Carcinogenesis Advance Access published online on March 16, 2006
Carcinogenesis, doi:10.1093/carcin/bgl013
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1 Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA
* To whom correspondence should be addressed. 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 ten oxidative stress genes (AKR1A1, AKR1C1, CYBA, GPX, MPO, NOS2A, NOS3, OGG1, PPARG, SOD2) were genotyped in 1,172 NHL cases and 982 population-based controls from a U.S. multi-center case-control study. For NHL and five subtypes (diffuse large B-cell, follicular, marginal zone, small lymphocytic, 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 (global p-value=0.003). Specifically, for nitric oxide synthase (NOS2A Ser608Leu, rs2297518) Leu/Leu homozygotes, there was a two-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 diffuse large B-cell lymphoma. 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-kB pathway may further reveal important clues for lymphomagenesis.
Received January 10, 2006
Revised February 23, 2006
Accepted March 7, 2006
MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
Polymorphisms in oxidative stress genes and risk for non-Hodgkin lymphoma
Sophia S. Wang 1 *,
Scott Davis 2,
James R. Cerhan 3,
Patricia Hartge 1,
Richard K. Severson 4,
Wendy Cozen 5,
Qing Lan 1,
Robert Welch 6,
Stephen J. Chanock 6,
and
Nathaniel Rothman 1
2 Fred Hutchinson Cancer Research Center and the University of Washington, Seattle, WA, USA
3 Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN, USA; University of Iowa, Iowa City, IA, USA
4 Karmanos Cancer Institute and Department of Family Medicine, Wayne State University, Detroit, MI, USA
5 University of Southern California, Los Angeles, CA, USA
6 Core Genotyping Facility, Advanced Technology Corporation, National Cancer Institute, Gaithersburg, MD, USA
Sophia S. Wang, E-mail: wangso{at}mail.nih.gov
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