Genetic variants of folate and methionine metabolism and PCNSL incidence in a German patient population

Functional genetic polymorphisms involved in folate and methionine metabolism play an important role in both DNA synthesis and methylation, and affect the risk of various malignancies including lymphoproliferative disorders such as systemic non-Hodgkin's lymphoma. In a retrospective analysis of 185 immunocompetent patients with primary central nervous system lymphoma (PCNSL) and 212 population controls we therefore investigated eight genetic polymorphisms affecting methionine metabolism for potential association with the development of PCNSL. We observed underrepresentation of the G-allele of the methyltetrahydrofolate homocysteine S-methyltransferase (MTR) c.2756A > G (D919G) missense polymorphism among PCNSL patients (P = 0.045; odds ratio (OR) = 0.65; 0.43-0.99). Furthermore, for the methylenetetrahydrofolate reductase (MTHFR) c.1298A > C (E429A) polymorphism the mutated C-allele was found more frequently among PCNSL patients than among population controls (P = 0.026; OR = 1.57; 1.05-2.34). There were no associations of the other polymorphisms investigated (MTHFR c.677C > T, transcobalamin 2 (Tc2) c.776C > G, cystathionin beta-synthase (CBS) c.844_855ins68, reduced folate carrier-1 (RFC-1) c.80G > A, thymidylate synthase (TYMS) 28-bp repeat, and dihydrofolate reductase (DHFR) c.594 + 59del19 bp) and the presence of PCNSL. This analysis is the largest to date to evaluate associations between genetic variants of folate and methionine metabolism and PCNSL. Our results suggest the hypothesis that folate and methionine metabolism is relevant to susceptibility to PCNSL.