Association of MTHFR and ABCB1 polymorphisms with MTX‐induced mucositis in Chinese paediatric patients with acute lymphoblastic leukaemia, lymphoma or osteosarcoma—A retrospective cohort study

Gong, Yan; Luo, Lei; Wang, Liu; Chen, Fen; Ma, Yuanyuan; Xu, Zhou; Sun, Yiqi; Luo, Lin; Chen, Shi; Li, Xingang

doi:10.1111/jcpt.13505

Cited by 11 publications

(9 citation statements)

References 30 publications

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“…Meanwhile, a significant association was also noticed between grade 3-4 mucositis and MTHFR rs1801133 polymorphism. Patients with C to T variants are more vulnerable to MTX-related mucositis, which was similar to a previous study ( 38 ). Particularly, a retrospective cohort study in Chinese pediatric patients revealed the close relevance of MTHFR rs1801133 polymorphism to mucositis ( 39 ).…”

Section: Discussionsupporting

confidence: 91%

“…Particularly, a retrospective cohort study in Chinese pediatric patients revealed the close relevance of MTHFR rs1801133 polymorphism to mucositis ( 39 ). In other conditions such as RA and hematological malignancies, a close relationship between MTHFR C677T polymorphism and risk of hepatic or gastrointestinal toxicities has also been demonstrated ( 38 , 40 , 41 ). Additionally, high-grade (grade 3-4) kidney toxicity was correlated with the heterozygote comparison (TC vs. CC) of rs1801133 polymorphism but not in other genotype contrasts.…”

Section: Discussionmentioning

confidence: 99%

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MTHFR Polymorphism Is Associated With Severe Methotrexate-Induced Toxicity in Osteosarcoma Treatment

et al. 2021

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BackgroundPrevious studies have revealed the critical role of methylene tetrahydrofolate reductase (MTHFR) polymorphisms in response to high-dose methotrexate (MTX)-induced toxicity in osteosarcoma patients. However, the conclusions remain controversial. In this setting, we performed a meta-analysis to determine their association more precisely.MethodEligible studies were searched and screened in PubMed, Web of Science, Cochrane Library, Clinical-Trials.gov, Embase, and China National Knowledge Infrastructure (CNKI) following specific inclusion and exclusion criteria. The required information was retrieved and collected for subsequent meta-analysis. Association between MTHFR polymorphism and MTX toxicity was evaluated by odds ratios (ORs).ResultsSeven studies containing 585 patients were enrolled and analyzed in this meta-analysis. Overall, the MTX related grade 3-4 liver toxicity was significantly associated with MTHFR rs1801133 allele (T vs. C: OR=1.61, 95%CI=1.07-2.42, P=0.024), homozygote (TT vs. CC: OR=2.11, 95%CI=1.06-4.21, P=0.011), and dominant genetic model (TT/TC vs. CC: OR=3.15, 95%CI=1.30-7.60, P=0.035) in Asian population. Meanwhile, close associations between MTX mediated grade 3-4 mucositis and MTHFR rs1801133 polymorphism were identified in allele contrast (T vs. C: OR=2.28, 95%CI=1.49-3.50, P<0.001), homozygote comparison (TT vs. CC: OR=4.07, 95%CI=1.76-9.38, P=0.001), heterozygote comparison (TC vs. CC: OR=2.55, 95%CI=1.20-5.42, P=0.015), recessive genetic model (TT vs. TC/CC: OR=2.09, 95%CI=1.19-3.67, P=0.010), and dominant genetic model (TT/TC vs. CC: OR=2.97, 95%CI=1.48-5.96, P=0.002). Additionally, kidney toxicity was corelated with the heterozygote comparison (TC vs. CC: OR=2.63, 95%CI=1.31-5.29, P=0.007) of rs1801133 polymorphism.ConclusionThe MTHFR rs1801133 polymorphism was significantly associated with severer liver toxicity induced by high-dose MTX treatment in the Asian population. In the meantime, patients with MTHFR rs1801133 polymorphism were predisposed to MTX- related mucositis.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

MTHFR Polymorphism Is Associated With Severe Methotrexate-Induced Toxicity in Osteosarcoma Treatment

et al. 2021

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“…Mucositis may be induced via different inflammatory responses, such as pro-inflammatory cytokines and folate metabolism pathway genes(18). Gong et al also confirmed that the CT+TT mutant genes can increase the mucosal toxicity of MTX(41). Thus, the MTHFR C677T gene polymorphism increases the risk of liver toxicity and mucosal damage in children with ALL treated with HD-MTX regimens.…”

mentioning

confidence: 99%

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

Tan¹,

Kong²,

Li³

et al. 2023

Transl Pediatr

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Background Acute lymphoblastic leukemia (ALL) is the most common malignancy in children, and methotrexate (MTX) is the key drug for ALL. Studies on the relationship between High-Dose methotrexate (HD-MTX) toxicity and methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C genes have drawn different conclusions. This study aimed to investigate the relationship between the polymorphism of MTHFR C677T and A1298C genes and the toxicity responses of MTX. Methods The MTHFR C677T and A1298C genotypes of 271 children with ALL who received HD-MTX chemotherapy in southern China from September 2017 to June 2021 were analyzed, and the toxicity of HD-MTX was evaluated and analyzed according to Common Terminology Criteria for Adverse Events (CTCAE) 5.0. Results The MTHFR C677T and A1298C gene polymorphisms were not correlated with the 48-hour MTX blood concentrations (P>0.05). Unconditional logistic regression model analysis also revealed that the risk of liver function impairment [odds ratio (OR) =1.656, 95% confidence interval (CI): 1.179–2.324, P<0.05] and mucosal damage (OR =1.508, 95% CI: 1.042–2.183, P<0.05) were 1.656 and 1.508 times higher for the heterozygous mutant (CT), and homozygous mutant (TT) mutant type than for the wild-type (CC), wild-type, respectively. The risk of neutropenia and liver function impairment were 0.498 (OR =0.498, 95% CI: 0.251–0.989, P<0.05) and 6.067 (OR =6.067, 95% CI: 1.183–31.102, P<0.05) times higher in low-risk children with CT+TT mutant genotypes than in those with CC wild genotypes, respectively. Furthermore, the risk of mucosal damage was 1.906 times higher in high-risk children with the CT+TT genotype than in those with the CC genotype (OR =1.906, 95% CI: 1.033–3.518, P<0.05). The MTHFR A1298C genotypes differed in the incidence of liver function damage and gastrointestinal toxic reactions in children with ALL. Nonetheless, no increased risk of liver function impairment nor gastrointestinal reactions in children with the heterozygous mutant (AC)+CC mutation was observed. Conclusions Advancements in MTHFR genotype testing in children with ALL and the introduction of personalised treatments based on genotype results during HD-MTX chemotherapy will help to predict, prevent, and reduce the occurrence of adverse MTX-related toxic reactions.

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“…One study was identified that focused on MTX induced mucositis [ 26 ]. The authors investigated 80 patients for 23 variants in 15 genes known to be involved in MTX processing in the body.…”

Section: Resultsmentioning

confidence: 99%

“…This included a search of the 91 genetic association studies identified during selection of the articles of the first systematic search performed on the 30th of September 2020. Thus the five papers identified during the updated search were not included [22][23][24][25][26]. In addition, PharmGKB and Pubmed were searched manually using the gene and variant of interest, doxorubicin and/or cardiotoxicity as search words.…”

Section: Follow-up Researchmentioning

confidence: 99%

Pharmacogenetics of chemotherapy treatment response and -toxicities in patients with osteosarcoma: a systematic review

Hurkmans¹,

Brand²,

Verdonschot

et al. 2022

BMC Cancer

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Background Osteosarcoma is the most common bone tumor in children and adolescents. Despite multiagent chemotherapy, only 71% of patients survives and these survivors often experience long-term toxicities. The main objective of this systematic review is to provide an overview of the discovery of novel associations of germline polymorphisms with treatment response and/or chemotherapy-induced toxicities in osteosarcoma. Methods MEDLINE and Embase were systematically searched (2010-July 2022). Genetic association studies were included if they assessed > 10 germline genetic variants in > 5 genes in relevant drug pathways or if they used a genotyping array or other large-scale genetic analysis. Quality was assessed using adjusted STrengthening the REporting of Genetic Association studies (STREGA)-guidelines. To find additional evidence for the identified associations, literature was searched to identify replication studies. Results After screening 1999 articles, twenty articles met our inclusion criteria. These range from studies focusing on genes in relevant pharmacokinetic pathways to whole genome sequencing. Eleven articles reported on doxorubicin-induced cardiomyopathy. For seven genetic variants in CELF4, GPR35, HAS3, RARG, SLC22A17, SLC22A7 and SLC28A3, replication studies were performed, however without consistent results. Ototoxicity was investigated in one study. Five small studies reported on mucosistis or bone marrow, nephro- and/or hepatotoxicity. Six studies included analysis for treatment efficacy. Genetic variants in ABCC3, ABCC5, FasL, GLDC, GSTP1 were replicated in studies using heterogeneous efficacy outcomes. Conclusions Despite that results are promising, the majority of associations were poorly reproducible due to small patient cohorts. For the future, hypothesis-generating studies in large patient cohorts will be necessary, especially for cisplatin-induced ototoxicity as these are largely lacking. In order to form large patient cohorts, national and international collaboration will be essential.

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Association of MTHFR and ABCB1 polymorphisms with MTX‐induced mucositis in Chinese paediatric patients with acute lymphoblastic leukaemia, lymphoma or osteosarcoma—A retrospective cohort study

Cited by 11 publications

References 30 publications

MTHFR Polymorphism Is Associated With Severe Methotrexate-Induced Toxicity in Osteosarcoma Treatment

MTHFR Polymorphism Is Associated With Severe Methotrexate-Induced Toxicity in Osteosarcoma Treatment

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

Pharmacogenetics of chemotherapy treatment response and -toxicities in patients with osteosarcoma: a systematic review

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