Methylenetetrahydrofolate reductase C677T and A1298C gene variants in adult non-Hodgkin's lymphoma patients: association with toxicity and survival

Abstract

Background and ObjectivesCommon methylenetetrahydrofolate reductase gene variants (MTHFR C677T and A1298C) have been described to have opposite effects on cancer patients. They may reduce cancer susceptibility and increase drug-related toxicity when folate antagonists (e.g. methotrexate) are utilized. We analyzed 110 patients with high-grade non-Hodgkin's lymphoma (NHL), 68 of whom were eligible for a chemotherapy combination containing methotrexate (MACOP-B) and 42 for chemotherapy without methotrexate (CHOP). Design and MethodsPatients were genotyped by polymerase chain reaction and stratified by MTHFR variants. These data were related to the toxicity (WHO grade GO-4) that the patients suffered and their survival. Overall 64 cases (58.2%) developed some form of toxicity and 23 (20.9%) had grade 3/4 toxicity. ResultsWhen considering toxicity of any grade (grade 1-4), the 677TT genotype was significantly over-represented among cases with mucositis (OR=4.85; 95%CI, 1. 47-15.97; p=0.009) and those with hepatic toxicity (OR=3.43; 95%CI, p=0.052). Sub-analyses in the group treated with MACOP-B showed a slight increase in the risk of developing mucositis (OR=5.22; 95%CI, p=0.03), and a strong increase in the risk of hepatic toxicity (OR=7.08; 95%CI, 1.38-36.2; p=0.019) and thrombocytopenia (OR=7.69, 95%CI 1. 0-58.94; p=0.05). Interestingly, compared to the risk of developing toxicity of any grade, the risk of developing severe (grade 3/4) mucositis was almost doubled in the whole group of cases with 677TT (OR=8.13; p=0.011) and dramatically increased in the MACOP-B-treated cases with this gene variant (OR=24.6; 95%CI 2. 49-87.41; p=0.001). There were significant results for 1298CC cases exclusively for mucositis (any grade, OR=5.33; 95%CI, p=0.023 and OR=9.15; 95%CI, p=0.037; for the whole group and the MACOP-B-treated group, respectively). Similarly, the risk of 1298CC patients developing severe mucositis increased (OR=9.24; 95%CI, 1. p=0.017 and OR=11.53; p=0.057; in the whole group and in the MACOP-B-treated group, respectively). Event-free survival analysis revealed a lower probability of event-free survival at 5 years for 677T-carriers (log-ranks, p=0.05 and p=0.07 in the whole group and in the MACOP-B-treated group, respectively). More significant results were obtained when 1298CC cases were excluded from the reference group (log-ranks, p=0.03 and p=0.04, respectively). No significant associations were found in the CHOPtreated group. Interpretation and ConclusionsOur data suggest that MTHFR gene variants play a critical role in NHL outcome, possibly by interfering with the action of methotrexate with significant effects on toxicity and survival. Genotyping of folate pathway gene variants might be useful to enable reduction of chemotherapy toxicity and/or to improve survival by indicating when dose adjustments or alternative treatments are necessary.Key words: non-Hodgkin's lymphoma, MTHFR SNP , toxicity, survival, pharmacogenetics. converts methylenetetrahydrofolate to methyltetrahydrofolate, the major ci...

The role of the MTHFR 677C>T polymorphism in methotrexate-induced liver toxicity: a meta-analysis in patients with cancer

“…Firstly, in four of the seven studies, MTX was given on a weekly basis with doses between 15 and 30 mg m À 2 for 2-3 years without leucovorin rescue. 7,9,17,18 In the other three studies, including this study, 4,16 MTX was administered at a dose of 4-14 g m À 2 . Sub-analysis according to MTX doses did, however, show absence of effect of the polymorphism in both the low-(15-30 mg m À 2 per course) and high-dose (4-14 g m À 2 per course) group.…”

“…The corresponding authors of six studies were willing to reclassify their data and stratify according to the NCI criteria as described above. 4,7,9,[16][17][18] However, this information was only available in a subset (N ¼ 1044) of all patients (N ¼ 1394) included in these seven studies, including our own study. Table 2 shows the conclusions of the initial studies, as well as the number of patients per study that were included in the meta-analysis.…”

Distribution of TYMS, MTHFR, p53 and MDR1 gene polymorphisms in patients with breast cancer treated with neoadjuvant chemotherapy

“…Severe toxicity to MTX has been reported with the implication of those polymorphisms [12]. MTHFR gene variants seem to play a critical role in non-Hodgkiń s lymphoma outcome, possibly by interfering with the action of MTX with significant effects on toxicity and survival [13]. Mutations in the p53 gene are the most common genetic alterations in human cancer [14].…”

Gene polymorphisms in folate metabolizing enzymes in adult acute lymphoblastic leukemia: effects on methotrexate-related toxicity and survival

“…The relationship between polymorphisms affecting folate metabolism and methotrexate-related toxicity has been studied mainly in childhood ALL, 2,[11][12][13][14][15] while only a few studies have investigated this relationship in adult patients with hematologic diseases. 16,17 In particular, in adult ALL only MTHFR polymorphisms have been investigated and associated with increased methotrexaterelated toxicity. 18,19 The aim of our study was to investigate the influence of polymorphisms directly involved in the methotrexate pharmacological pathway in relation to the outcome of adult ALL patients treated with methotrexate maintenance therapy.…”