RAD51 homologous recombination repair gene haplotypes and risk of acute myeloid leukaemia.

Homologous recombination (HR) is one of the main pathways for the repair of DNA double strand breaks (DSBs). To investigate whether inherited variants in genes encoding proteins that repair DSBs by HR modulate acute myeloid leukaemia (AML) risk, we have examined the frequency of two variants in the 5' untranslated region (UTR) of RAD51 (RAD51 135 G>C and the RAD51 172 G>T) in a large case-control study of acute myeloid leukaemia (AML). Inheritance of a RAD51 135 C allele was associated with a reduced risk of estimate for AML (odds ratio (OR) 0.56, 95% confidence intervals (CI), 0.38-0.83), while the RAD51 172 T allele was not associated with AML. The RAD51 135 and 172 variants were in strong linkage disequilibrium, with three out of the four possible haplotypes being observed in the population. The protective effect associated with the RAD51 135 C allele was found to be associated with inheritance of the RAD51 135-172 C-G haplotype (cases 3.9% versus controls 6.5%, OR 0.61, 95% CI 0.42-0.90). These data suggest that variants in the RAD51 HR gene may modulate genetic predisposition to AML.

Polymorphisms in the oxidative stress genes, superoxide dismutase, glutathione peroxidase and catalase and risk of non-Hodgkin's lymphoma.

BACKGROUND AND OBJECTIVES: The risk of non-Hodgkin's lymphoma (NHL) has been associated with inflammation. One possible mechanism may involve oxidative stress as reactive oxygen species (ROS) can generate pro-inflammatory signals. Anti-oxidant enzymes including superoxide dismutase, glutathione peroxidase and catalase protect against the harmful effects of ROS. Genetic variation in the genes coding for these enzymes (SOD2, GPX1, and CAT, respectively) alters ROS production and therefore may provide a mechanism for the relationship between inflammation and NHL. DESIGN AND METHODS: Data from two population-based, case-control studies of lymphoma in the UK (700 cases and 915 controls) and USA (1593 cases and 2517 controls) were pooled to analyze polymorphisms in genes involved in the oxidative stress response (SOD2 Val16Ala, CAT C-262T and GPX1 Pro197Leu). RESULTS: No associations were observed between SOD2 Val16Ala and CAT C-262T and total NHL, diffuse large-B cell lymphoma or follicular lymphoma. However, when we looked at marginal zone lymphoma, a specific subtype of lymphoma characterised by inflammation, we found that homozygosity for the SOD2 16Ala allele was associated with a decreased risk among UK study participants. The GPX1 197Leu allele was weakly associated with NHL and follicular lymphoma. INTERPRETATION AND CONCLUSION: Analysis of genetic variation in oxidative stress genes in two lymphoma case-control studies suggests a possible role for oxidative stress in the risk of NHL. The risk modification is seen predominantly for marginal zone lymphomas which frequently arise in the context of chronic inflammation. However, in order to clarify the role of oxidative stress in the etiology of NHL analyses of additional polymorphisms and haplotypes in these and other genes involved in the oxidative stress response are needed.

Risk of non-Hodgkin lymphoma associated with polymorphisms in folate-metabolizing genes.

Genetic instability, including chromosomal imbalance, is important in the pathogenesis of lymphoproliferative disorders such as non-Hodgkin lymphoma (NHL). DNA synthesis and methylation, which are closely linked to folate metabolism and transport, may be affected by polymorphisms in genes involved in these pathways. Folate metabolism polymorphisms have been linked to acute lymphoblastic leukemia and colorectal cancer. To evaluate whether genetic variation in folate metabolism and transport may have a role in determining the risk of developing NHL, we analyzed several polymorphisms using DNA obtained as part of a large U.K. population-based case-control study of lymphoma. Polymorphisms studied include methylenetetrahydrofolate reductase (MTHFR) 677 C >T and 1298 A >C, methionine synthase (MTR) 2756 A>G, serine hydroxymethyltransferase (SHMT1) 1420 C >T, thymidylate synthase (TYMS) 1494del6 and 28-bp repeat, and reduced folate carrier (RFC) 80 G >A. Increased risks for NHL [odds ratio (OR), 1.48; 95% confidence intervals (CI), 1.12-1.97], and marginal zone lymphoma (OR, 3.38; 95% CI, 1.30-8.82) were associated with the TYMS 2R/3R variant. Marginal increased risks were also observed for diffuse large B cell lymphoma with the TYMS homozygous 6 bp deletion (OR, 1.61; 95% CI, 0.99-2.60) and for follicular lymphoma with RFC 80AA (OR, 1.44; 95% CI, 0.94-2.22) and TYMS 28-bp repeat 2R/3R (OR, 1.45; 95% CI, 0.96-2.2). We observed no association between NHL and haplotypes for MTHFR or TYMS. These findings are somewhat inconsistent with those of others, but may reflect differences in circulating folate levels between study populations. Thus, further investigations are warranted in larger series with dietary information to determine the roles that genetics and folic acid status play in the etiology of lymphoma.

Polymorphisms in the nucleotide excision repair gene ERCC2/XPD and risk of non-Hodgkin lymphoma.

Non-Hodgkin lymphoma (NHL) represents a complex group of B- and T-cell malignancies characterised by chromosomal translocations. Since defects in DNA repair result in an increased frequency of chromosomal aberrations it has been hypothesised that genetic variation in DNA repair may be associated with risk of NHL. To investigate the relationship between DNA repair and NHL we analysed polymorphisms in XPD (R156R, D312N, K751Q) using DNA collected in a UK population-based case-control study of lymphoma. We observed no association between genetic variation in XPD and risk of NHL. However, the XPD 751 Gln allele was associated with a two-fold decreased risk of diffuse large B-cell lymphoma (OR 0.56, 95% CI 0.34-0.92, p=0.02), the major subtype of NHL. Overall, our study identifies that XPD polymorphisms may be important in the aetiology of NHL although analysis of additional polymorphisms and extended haplotype studies are required to clarify their role.

Haplotypes in the tumour necrosis factor region and myeloma.

This study described the haplotypic structure across a region of chromosome 6 including the tumour necrosis factor (TNF) gene, and investigated its influence on the aetiology of myeloma. A total of 181 myeloma cases from the Medical Research Council Myeloma VII trial and 233 controls from the Leukaemia Research Fund Case Control Study of Adult Acute Leukaemia were included in the analysis. Genotyping by induced heteroduplex generator analysis was carried out for single nucleotide polymorphisms (SNP) located at positions -1031, -863, -857, -308 and -238 of the 5' promoter region of TNF-alpha gene, and 252 in the LT-alpha gene; and five microsatellites, TNFa, b, c, d and e. Haplotypes were inferred statistically using the phase algorithm. A limited diversity of haplotypes was observed, with the majority of variation described by 12 frequent haplotypes. Detailed characterization of the haplotype did not provide greater determination of disease risk beyond that described by the TNF-alpha-308 SNP. Some evidence was provided for a decreased risk of myeloma associated with the TNF-alpha-308 variant allele A, odds ratio, 0.57; 95% confidence interval, 0.38-0.86. The results of this study did not support our starting hypothesis; that high producer haplotypes at the TNF locus are associated with an increased risk of developing myeloma.

Polymorphic variation in GSTP1 modulates outcome following therapy for multiple myeloma.

Glutathione S-transferase P1 (GSTP1) is a phase 2 drug metabolism enzyme involved in the metabolism and detoxification of a range of chemotherapeutic agents. A single nucleotide polymorphism (Ile105Val) results in a variant enzyme with lower thermal stability and altered catalytic activity. We hypothesized that patients with the less stable variant have a decreased ability to detoxify chemotherapeutic substrates, including melphalan, and have an altered outcome following treatment for multiple myeloma. We have assessed the impact of GSTP1 codon 105 polymorphisms in 222 patients entered into the Medical Research Council (MRC) myeloma VII trial (comparing standard-dose chemotherapy with high-dose therapy). In the standard-dose arm, patients with the variant allele (105Val) had an improved progression-free survival (PFS) (adjusted hazard ratios for PFS were 0.55 for heterozygotes and 0.52 for 105Val homozygotes, compared with 105Ile homozygotes; P for trend =.04); this was supported by a trend to improved overall survival, greater likelihood of entering plateau and shorter time to reach plateau in patients with the 105Val allele. No difference in outcome by genotype was found for patients treated with high-dose therapy. However, the progression-free survival advantage of the high-dose arm was seen only in patients homozygous for 105Ile (P =.008).