One-carbon metabolism gene polymorphisms and risk of non-Hodgkin lymphoma in Australia
Dysregulation of the one-carbon metabolic pathway, which controls nucleotide synthesis and DNA methylation, may promote lymphomagenesis. We evaluated the association between polymorphisms in one-carbon metabolism genes and risk of non-Hodgkin lymphoma (NHL) in a population-based case-control study in Australia. Cases (n = 561) and controls (n = 506) were genotyped for 14 selected single-nucleotide polymorphisms in 10 genes (CBS, FPGS, FTHFD, MTHFR, MTHFS, MTR, SHMT1, SLC19A1, TCN1, and TYMS). We also conducted a meta-analysis of all studies of Caucasian populations investigating the association between MTHFR Ex5+79C > T (a.k.a., 677C>T) and NHL risk. A global test of 13 genotypes was statistically significant for diffuse large B-cell lymphoma (DLBCL; P = 0.008), but not for follicular lymphoma (FL; P = 0.27) or all NHL (P = 0.17). The T allele at MTHFR Ex5+79 was marginally significantly associated with all NHL (OR = 1.25, 95% CI = 0.98–1.59) and DLBCL (1.36, 0.96–1.93). The T allele at TYMS Ex8+157 was associated with a reduced risk of FL (0.64, 0.46–0.91). An elevated risk of NHL was also observed among carriers of the G allele at FTHFD Ex21+31 (all NHL, 1.31, 1.02–1.69; DLBCL, 1.50, 1.05–2.14). A meta-analysis of 11 studies conducted in Caucasian populations of European origin (4,121 cases and 5,358 controls) supported an association between the MTHFR Ex5+79 T allele and increased NHL risk (additive model, P = 0.01). In conclusion, the results of this study suggest that genetic polymorphisms of one-carbon metabolism genes such as MTHFR and TYMS may influence susceptibility to NHL.
KeywordsAcute Lymphoblastic Leukemia False Discovery Rate Australian Capital Territory False Positive Report Probability Uracil Misincorporation
We gratefully acknowledge the individuals who participated in the research, the clinicians who gave permission for us to approach their patients, and staff at the NSW Central Cancer Registry and the Hunter Valley Research Foundation. Special thanks to Melisa Litchfield, Maria Agaliotis, and Chris Goumas for data collection and data entry and to Jackie Turner for telephone follow-up. We also thank Robert Welch and Sunita Yadavalli at the NCI Core Genotyping Facility for their work in the specimen handling and laboratory analysis of genotyping data. This research was supported by the Intramural Research Program of the NIH and the National Cancer Institute. Bruce Armstrong’s research is supported by a University of Sydney Medical Foundation Program Grant. The principal investigator of the population-based case-control study in New South Wales, Australia is B.K.A.; the recruitment of subjects and sample collection were performed by A.K., A.E.G., C.M.V, and J.T.; the one-carbon metabolism project was initiated and conducted by Q.L., N.R., M.P.P., and D.K.; D.W.’s laboratory performed the DNA extraction and genotyping at the NCI Core Genotyping Facility was supervised by S.C.; the statistical analysis was performed by K.M.L. and M.P.P.; the paper was drafted and revised by K.M.L., M.P.P., Q.L., N.R., and B.K.A.; and all authors reviewed and approved the paper.
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