ASSOCIATION BETWEEN METHOTREXATE TOXICITY AND GENETIC VARIANTS OF METHIONINE AND FOLATE METABOLISM RELATED GENES IN PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA PATIENTS

Abstract BACKGROUND Methotrexate (MTX) is the backbone of therapy for primary central nervous system lymphoma (PCNSL). There have been conflicting results over whether polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) and transcobalamin 2 (TCN2) genes modulate MTX-associated toxicity. METHODS This is a retrospective study involving patients who underwent MTX-based chemotherapy for PCNSL and were genotyped for polymorphisms in the MTHFR (Ala222Val, C >T; Glu429Ala, A >C) and TCN (Arg259Pro, C >T) genes as part of a separate study investigating the association of genetic risk factors for treatment-related cognitive dysfunction. Renal, hepatic, and bone marrow toxicities were graded according to CTCAEv5.0, and only toxicities grade 3 or higher were considered clinically significant. MRIs of the brain during and after MTX treatment were rated for white matter changes (WMC) and cortical atrophy (CA). Genotypes were cross-tabulated with toxicities and worsening of WMC and CA. Associations were tested using Fisher’s exact tests. RESULTS We identified 35 PCNSL patients treated with MTX and had available genotyping data. 18 patients (51%) carried one or more MTHFR-T (c.222 Val) alleles, 16 patients (46%) had one or more MTHFR- C (c.429 Ala) alleles, and 30 patients (86%) had one or more TCN-G (c. 259 Pro) alleles. Bivariate analysis revealed that the MTHFR-T (c.222Val) allele was associated with increased hepatotoxicity (p=0.03). None of the polymorphisms tested were associated with renal or bone marrow toxicity. Though changes in CA were observed, the association of polymorphisms with WMC or CA did not reach statistical significance, potentially confounded by small sample size and limited sensitivity of rating scales. CONCLUSION These preliminary observations suggest that the Val on codon 222 of the MTHFR gene might be involved in the modulation of toxicity, however a larger study is required to assess whether variants involved in methionine metabolism may influence MTX-associated hepatotoxicity in PCNSL patients.