Influence of Methylenetetrahydrofolate Reductase C677T and A1298C Polymorphism on High-Dose Methotrexate-Related Toxicities in Pediatric Non-Hodgkin Lymphoma Patients

Abstract

PurposeThis retrospective study aimed to investigate the relationships between the methylenetetrahydrofolate reductase (MTHFR) C677T/A1298C and high-dose methotrexate (HD-MTX)-related toxicities in pediatric non-Hodgkin lymphoma (NHL) patients.Patients and MethodsWe reviewed the medical records of 93 NHL patients aged under 18 years who received HD-MTX therapy at the dose of 5 g/m2 with 24-h infusion at Sun Yat-sen University Cancer Center between 2014 and 2019.ResultsThere were 61 males and 32 females, with a median age of 8.8 years (0.9–15.8 years). The tumor types included lymphoblastic lymphoma (n = 38), Burkitt’s lymphoma (n = 31), anaplastic large cell lymphoma (n = 18), diffuse large B-cell lymphoma (n = 6). Overall, 355 courses of HD-MTX therapy were prescribed. All patients were rescued with calcium folinate 12 h after the end of MTX infusion. We found that plasma MTX levels > 0.2 μmol/L at 48 h post-infusion increased the risk of developing oral mucositis (2.4% VS. 9.5%, P = 0.018). Also, patients carrying the C677T and T677T genotypes had tendencies to be more susceptible to oral mucositis (P = 0.034). Patients harboring mutant 677T allele were more likely to develop leucopenia (38.5 vs. 50.3%, P = 0.025) and thrombocytopenia (22.0 vs. 32.4%, P = 0.028). For polymorphism A1298C, the mutant genotype played a protective role in vomiting (11.1 vs. 4.3%, P = 0.018) but increased the risk of anemia (23.8 vs. 41.7%, P < 0.001) and leucopenia (38.1 vs. 50.3%, P = 0.021).ConclusionChildhood NHL patients harboring C677T genotype were more vulnerable to oral mucositis, leucopenia, and thrombocytopenia, while those with A1298C genotype were at a decreased risk of vomiting and more likely to develop anemia and leucopenia.

Relationship between methylenetetrahydrofolate reductase gene polymorphisms and methotrexate drug metabolism and toxicity

“…Thus, mutant genes are considered to induce a protective effect against mucosal damage, whereas wild-type genes are more likely to cause mucosal damage ( 39 ). In contrast, some studies also reported that C677T mutant genes are strongly associated with grade III or higher mucosal toxicity, thereby causing oral mucositis ( 28 , 29 , 40 ). In the present study, patients with the CT+TT mutant phenotype were more prone to mucosal damage in the high-risk group, but no correlation was observed in the low- and intermediate-risk groups.…”

“…Thus, mutant genes are considered to induce a protective effect against mucosal damage, whereas wildtype genes are more likely to cause mucosal damage (39). In contrast, some studies also reported that C677T mutant genes are strongly associated with grade III or higher mucosal toxicity, thereby causing oral mucositis (28,29,40).…”

Genetic polymorphisms of genes involved in oxidative stress and inflammatory management in oncopediatric patients with chemo-induced oral mucositis

“…32 Our study focused on exploring different genetic polymorphisms than those commonly analyzed in the context of chemo-induced OM, which are usually related to drug metabolism. [14][15][16] To our knowledge, this is the first study investigating rs4880, rs7943316, rs1800629, and rs1800795 in a group of pediatric cancer patients with OM since it was not possible to obtain information about the distribution of these polymorphisms in other pediatric populations presenting this outcome. This demonstrates the importance of more studies in this area.…”

“…Single-nucleotide polymorphisms (SNPs) in genes involving drug metabolism (ABCC2, rs717620; MTHFR, rs1801133; ABCG2 rs2231137) and cell signaling pathways (miR-1206, rs2114358) have been associated with the incidence of chemo-induced OM in pediatric blood cancer patients. [14][15][16][17] However, there are no reports on the relation between SNPs in genes involving antioxidant enzymes and chemo-induced OM in any population. Regarding polymorphisms in cytokine genes in the same context, reports are limited to studies involving adults.…”

Polymorphism but not methylation status in the vitamin D receptor gene contributes to oral mucositis in children

“…Studies addressing genetic markers such as single nucleotide polymorphisms (SNPs) in the context of oral mucositis in oncopaediatric patients have already been conducted in China (Lu et al, 2021), the Netherlands (Den Hoed et al, 2015; Gutierrez‐Camino et al, 2017; Oosterom, Berrevoets, et al, 2018), Mexico (Ruiz‐Argüelles et al, 2007) and Turkey (Bektaş‐Kayhan et al, 2012), among others. We are the only group to date to conduct studies of this nature in Brazil (Coêlho et al, 2022; Viana Filho et al, 2021).…”