The methionine synthase polymorphism D919G alters susceptibility to primary central nervous system lymphoma

Primary central nervous system lymphomas (PCNSL) frequently reveal genomic instability. The human methionine-homocysteine metabolism is important for genomic integrity due to a key position in folate-dependent DNA methylation and synthesis. We have previously suggested a protective function of the functional polymorphism methionine synthase c.2756A>G (D919G) against the incidence of primary central nervous system lymphoma (Brit J Cancer, in press). Here we present a confirmation of the assumed association by the analysis of an extended patient sample. In total, 43 PCNSL patients were compared to 142 age and sex matched controls. 8 patients (19%) carried the methionine synthase polymorphism c.2756A>G as opposed to 59 control subjects (42%; OR=0.32 [95%CI: 0.13–0.79]; p[Chi2]=0.006; relative risk=0.40 [95%CI: 0.18–0.83]). We conclude that this polymorphism, which had already been shown to protect against colorectal cancer and types of systemic NHL in other studies (Br J Haematol 2003;120:1051–1054; Cancer Epidemiol Biomarkers Prev 1999;8:825–829), indeed is of protective character against PCNSL. Thus, the metabolic kinetics which are influenced by this polymorphism (folate-dependent DNA methylation and folate-dependent DNA synthesis) are attractive candidates for the investigation of the susceptibility to PCNSL and other cancers and for preventive strategies.