Obesity, diet and risk of non-Hodgkin lymphoma

Abstract

Non-Hodgkin lymphoma (NHL) represents a group of heterogeneous diseases that significantly vary in their causes, molecular profiles, and natural progression. In 2007, there will be approximately 59,000 newly diagnosed NHL cases in the United States and over 300,000 cases worldwide. Although new therapeutic regimens are minimizing the number of deaths related to NHL, causes for the majority of lymphomas remain undetermined. Recent studies suggest that dietary factors may contribute to the rising rates of NHL. This review will summarize epidemiologic reports that have studied the relationship between obesity, physical activity, and diet and risk of NHL. Based on a number of case-control and prospective cohort studies, overweight/obesity probably increases the risk of NHL, whereas moderate physical activity may reduce risk. Several studies support an inverse association between intakes of vegetables and NHL risk, particularly for the consumption of cruciferous vegetables. This may relate to the induction of apoptosis and growth arrest in preneoplastic and neoplastic cells, two important actions of isothiocyanates found in cruciferous vegetables. Studies also suggest that fish intake may be inversely associated with risk of NHL, although findings have not been entirely consistent. This may relate to the high organochlorine content in some fish that could override a protective effect. High consumption of fats, meat, and dairy products also may increase lymphoma risk. The accumulated scientific evidence concerning the associations between obesity, diet, and NHL suggests several identified modifiable risk factors that might be recommended to decrease lymphoma risk.

Figure 1. Mechanisms of apoptosis and growth arrest by isothiocyanates

Isothiocyanates induce apoptosis and growth arrest involving a number of mechanisms, which may be particularly relevant in preventing lymphomagenesis and other neoplasms. Some potential mechanisms may involve their ability to inhibit the anti-apoptotic proteins, Bcl-2 and Bcl-x, and up-regulate the pro-apoptotic molecules, Bax and Bak, initiating apoptotic cell death through cytochrome c release and the subsequent activation of caspases. Isothiocyanates also can promote apoptotic cell death through the up-regulation of c-Jun N-terminal kinase (JNK) and down-regulation of nuclear factor (NF)-κB signaling pathways. These compounds also may induce cell cycle arrest by the induction of activator protein 1 (AP-1) resulting in up-regulation of the cyclin-dependent kinase (CDK) inhibitor, p21, and subsequent G(2)/M arrest.

Figure 2. Overview of the folate metabolic pathway

Abnormal one-carbon metabolism, either through folate deficiency or through polymorphisms in folate metabolizing genes, may promote lymphomagenesis through mechanisms involving aberrant DNA synthesis, repair and methylation (hypomethylation of proto-oncogenes or hypermethylation of tumor suppressor genes). A 677C>T (222Ala>Val) polymorphism in the MTHFR gene, associated with reduced MTHFR enzyme activity, may cause DNA hypomethylation while increasing the flux of one-carbon units available for purine and DNA synthesis and repair. Reduced TYMS enzyme activity may increase uracil incorporated in DNA and result in chromosome damage and fragile site induction. A 28-bp double repeat in the promoter region and a 6-bp deletion in the 3′UTR of the TYMS gene alter TYMS gene expression and mRNA stability, that can influence the rate of DNA double strand breaks and chromosomal translocations. S-adenosylmethionine (SAM); S-adenosylhomocysteine (SAH); tetrahydrofolate (THF); serine hydroxymethyltransferase (SHMT); 5,10-methylenetetrahydrofolate (5,10-methyleneTHF); 5,10-methylenetetrahydrofolate reductase (MTHFR); 5-methyltetrahydrofolate (5-methylTHF); methionine synthase (MTR); thymidylate synthase (TYMS); deoxythymidine monophosphate (dTMP); and deoxyuridine monophosphate (dUMP).