Genetic susceptibility to lymphoma

Abstract

Genetic susceptibility studies of lymphoma may serve to identify at risk populations and clarify important disease mechanisms. This review considered all studies published through October 2006 on the contribution of genetic polymorphisms in the risk of lymphoma. Numerous studies implicate the role of genetic variants that promote B-cell survival and growth with increased risk of lymphoma. Several reports including a large pooled study by InterLymph, an international consortium of non-Hodgkin lymphoma (NHL) case-control studies, found positive associations between variant alleles in TNF -308G>A and IL10 -3575T>A genes and risk of diffuse large B-cell lymphoma. Four studies reported positive associations between a GSTT1 deletion and risk of Hodgkin and non-Hodgkin lymphoma. Genetic studies of folate-metabolizing genes implicate folate in NHL risk, but further studies that include folate and alcohol intakes are needed. Links between NHL and genes involved in energy regulation and hormone production and metabolism may provide insights into novel mechanisms implicating neuro- and endocrine-immune cross-talk with lymphomagenesis. However, this links will need replication in larger populations. Numerous studies suggest that common genetic variants with low penetrance influence lymphoma risk, though replication studies will be needed to eliminate false positive associations.

Figure 1. The normal life cycle of B-lymphocytes and the derivation of lymphoma subtypes

During normal B-cell development, hematopoietic stem cells first colonize the bone marrow and give rise to common lymphoid progenitor cells, some of which will differentiate to B-cell lineage. While in the bone marrow, V(D)J recombination machinery rearranges germline immunoglobulin (Ig) gene loci that lead to formation of chromosomal translocations. Mature naïve B-cells that express the B-cell receptor exit the bone marrow to lymph nodes and extra-lymphatic follicles. There, upon antigenic stimulation, B-cells become activated undergoing a proliferative burst, generating formation of germinal centers (GCs). In GCs, proliferating B-cells are subjected to somatic hypermutation, directed at Ig genes. In GCs, the most common aggressive lymphoma, diffuse large B-cell lymphoma (DLCL), can originate from activated B-cells, otherwise known as centroblasts, and the most common indolent lymphoma, follicular lymphoma (FL), can derive from centrocytes. FL also can transform to DLCL. Burkitt's lymphoma can derive from IgM-positive blasts of the early GC reaction. Some B-cells in GCs will further differentiate into memory cells while others will become plasma cells, of which multiple myeloma can derive. Mantle zone lymphomas and some small lymphocytic lymphomas have unmutated V-region genes suggesting they originate from naïve peripheral B-cells. Class switch recombination permits B-cells to switch from membrane-bound to soluble B-cell receptors and also acts aberrantly to cause chromosomal translocations.

Figure 1 online. Overview of the folate metabolic pathway

S-adenosylmethionine (SAM); S-adenosylhomocysteine (SAH); tetrahydrofolate (THF); serine hydroxymethyltransferase (SHMT); 5,10-methylenetetrahydrofolate (methyleneTHF); 5,10-methylenetetrahydrofolate reductase (MTHFR); 5-methyltetrahydrofolate (methylTHF); methionine synthase (MTR); thymidylate synthase (TYMS); deoxythymidine monophosphate (dTMP); and deoxyuridine monophosphate (dUMP).

Figure 1 online. Overview of the folate metabolic pathway

S-adenosylmethionine (SAM); S-adenosylhomocysteine (SAH); tetrahydrofolate (THF); serine hydroxymethyltransferase (SHMT); 5,10-methylenetetrahydrofolate (methyleneTHF); 5,10-methylenetetrahydrofolate reductase (MTHFR); 5-methyltetrahydrofolate (methylTHF); methionine synthase (MTR); thymidylate synthase (TYMS); deoxythymidine monophosphate (dTMP); and deoxyuridine monophosphate (dUMP).

Figure 2. Nf-κB pathways and downstream factors affecting lymphoma risk

Signaling through TNFRs, IL1R, TLRs and TCR leads to the activation of NF-κB. Genetic factors such as variants in TLR4, TNF, LEP and exogenous and endogenous factors such as microbial infections, oxidative stress and obesity may promote chronic inflammation and enhance cell survival by up-regulating proinflammatory cytokines such as TNF-α, IL-6, IL-1 and leptin. Activation of the NF-κB pathway can enhance transcription of anti-apoptotic mediators such as Bcl-2L1, Bcl-2A1, cIAPs, and SOD2 and proliferative factors such as cyclinD1, cyclinD2, and c-MYC (38). Promotion of cell proliferation and survival of mutated cells including those with aberrantly rearranged antigen-receptors may contribute to lymphomagenesis. Tumor necrosis factor receptors (TNFRs), interleukin-1 receptor (IL1R), toll-like receptors (TLRs), T-cell receptor (TCR), nuclear factor kappa B (NF-κB), cyclooxygenase-2 (Cox-2), B-cell CLL/lymphoma 2-like 1 (Bcl-2L1), cellular Bcl2-related protein A1 (Bcl2A1), inhibitor-of-apoptosis proteins (cIAPs), superoxide dismutase-2 (SOD2), caspase recruitment domain family, member 15 (CARD15), nuclear factor kappa B inhibitor alpha (NFKBIA), interleukin-10 (IL10), IL-10 receptor alpha (IL10RA), tumor necrosis factor (TNF), leptin (LEP), interleukin-6 (IL6), cyclin-D1 (CCND1).

Figure 3. Environmental and genetic influences on fate of a naive mature B-cell encountering antigen

In early and late stages of B-cell development, genetic polymorphisms and environmental exposures influence the fate of a B-cell and its chances of undergoing neoplastic transformation. Genetic polymorphisms that influence DNA repair (▲) such as XRCC3 and TYMS can increase the likelihood of chromosomal translocations and mutations that occur during normal B-cell maturation and as a result of genotoxic environmental exposures or endogenous genotoxic processes including class switch recombination and somatic cell hypermutation. Polymorphisms that impair DNA methylation (•) such as in the MTHFR and MTR genes may promote lymphoma by mechanisms involving hypo- or hypermethylation of proto-oncogenes or tumor suppressor genes. SNPs in genes that deliver positive signals for B-cell growth and survival (◆), such as in TNF, LEP and CYP17A1, or that block differentiation (■), such as in BCL-6, can enhance immortalization of B-cells. Oxidative stress genes such as superoxide dismutase (SOD2 and NOS2A) (★) may influence whether cells are protected from the harmful effects of reactive oxygen species. Chronic antigenic stimulation of B-cells, through infection or proinflammatory conditions such as autoimmune disease or obesity, can activate B-cells and enhance their proliferation and survival. For lymphoma, this may be particularly relevant to growth, survival and ultimate transformation of B-cells that already carry pre-neoplastic lesions. SNPs can exacerbate these inflammatory responses (i.e., in pro-inflammatory cytokines, oxidative stress genes). The consistent associations found between B-cell NHL with genetic variants in pro-inflammatory factors such as TNF and leptin, and the association of viral, bacterial, and other exogenous agents leading to persistent inflammation, suggest this as one relevant mechanism underlying lymphomagenesis.