Methylenetetrahydrofolate reductase C677T and A1298C gene variants in adult non-Hodgkin lymphoma patients: association with clinical outcome

Several studies show that methylenetetrahydrofolate reductase gene variants (MTHFR C677T and A1298C) influence the risk of haematological malignancies. Further, a role for MTHFR C677T and A1298C on drug-related toxicity when folate antagonists are used (i.e. methotrexate; MTX) has been suggested. To evaluate the association between MTHFR gene variants and clinical outcome in high-grade non-Hodgkin’s lymphoma (NHL) we analysed 110 adult patients (whole group), 68 eligible for chemotherapy regimen with MTX (MACOP-B group) and 42 without MTX (CHOP group). Patients were PCR-genotyped, scored by G0-4 WHO toxicity (mucositis, anemia and hepatic, thrombocytic, lymphocytic toxicity), evaluated for survival and the associations were statistically analysed. In the whole group, by considering any toxicity grade (G1-4), 677TT genotype was significantly over-represented among cases with mucositis (OR=4.85; 95%CI, 1.47-15.97) or with hepatic toxicity (OR=3.43; 95%CI, 0.99-11.86). In the MACOP-B group, 677TT NHL cases showed increased risk of developing mucositis (OR=5.22; 95%CI, 1.20-27.27) hepatic (OR=7.08; 95%CI, 1.38-36.2) and thrombocytic toxicity (OR=7.69, 95%CI 1.0-58.94). Interestingly, the risk to develop severe (G3-4) mucositis for 677TT cases almost doubled in the whole group (OR=8.13; 95%CI 1.61-41.04) and drastically increased in the MACOP-B group (OR=24.6; 95%CI 2.49-87.41) compared to risk values found when any toxicity grade was computed. Significant results were obtained in 1298CC cases exclusively for mucositis, considering both any grade (OR=5.33; 95%CI, 1.25-22.70 and OR=9.15; 95%CI, 1.14-73.41 respectively for whole and MACOP-B group) and severe mucositis (OR=9.24; 95%CI, 1.47-58.0 and OR=11.53; 0.93-143.18 respectively for whole and MACOP-B group). Event free survival (EFS) analysis at five-years of follow-up, yielded a lower EFS probability for 677T-carriers (log-ranks, P=0.05 and P=0.07 respectively in the whole and in the MACOP-B group). More significant results were obtained when 1298CC cases were excluded from the reference group (log ranks, P=0.03 and P=0.04 respectively). Analyses of both toxicity and EFS yielded no significant associations in the CHOP group. Our data suggest a critical role for MTHFR gene variants in NHL outcome possibly by interference with MTX action. Genotyping of folate pathway gene variants might be useful to reduce chemotherapy toxicity and/or to improve survival by means of dose adjustments or alternative treatments.