Genetic variants associated with methotrexate-induced mucositis in cancer treatment: A systematic review and meta-analysis

Maagdenberg, Hedy; Oosterom, Natanja; Zanen, Jolanda; Gemmati, Donato; Windsor, Rachael; Heil, Sandra G.; Esperón, Patricia; Jabeen, Shakila; Ruíz‐Argüelles, Guillermo J.; Zolk, Oliver; Hoerning, Susanne; Sleurs, Charlotte; López-López, Elixabet; Moreno-Galván, Mónica; Heuvel‐Eibrink, Marry M. van den; Zee, Anke‐Hilse Maitland‐van der; Carleton, Bruce

doi:10.1016/j.critrevonc.2021.103312

Cited by 14 publications

(10 citation statements)

References 74 publications

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“…The most investigated clinical outcomes were hepatic toxicity and mucositis, followed by renal toxicity, while prognostic outcomes were reported by a small proportion of studies (14/ 34). Generally speaking, our study confirmed that the MTHFR 677C>T (rs1801133) has a significant effect on the increased risk of HDMTX toxicities (including hepatotoxicity, mucositis, and renal toxicity), and the ABCB1 3435C>T (rs1045642) has a significant effect on the increased risk of hepatotoxicity, which corresponds to the findings in previous studies (Yang et al, 2012;Zhao et al, 2016;Zhu et al, 2018;Yao et al, 2019;Maagdenberg et al, 2021), whereas we found a tendency toward reduced risk of hepatotoxicity in carriers of RFC1 80GG and toward reduced risk of mucositis in those with TYMS 3R3R or 2R3R genotypes. Also, a tendency toward reduced risk of renal toxicity was observed in carriers with the MTHFR 1298 variant C allele, which was similar to the results of mucositis and GI toxicity (Zhao et al, 2016) and dermal toxicity (Yang et al, 2012).…”

Section: General Findings and Trendssupporting

confidence: 91%

“…After performing an update search and review in July 2021, we found six similar metaanalyses (Yang et al, 2012;Lopez-Lopez et al, 2013;He et al, 2014;Zhao et al, 2016;Oosterom et al, 2018;Yao et al, 2019) had a discussion on this issue in patients with hematological malignancies. Besides, three meta-analyses (Hagleitner et al, 2014; Zhu et al, 2018;Maagdenberg et al, 2021) included cancer patients and did not distinguish between hematological malignancies and osteosarcoma, although the dosage and infusion regimens of HDMTX vary greatly in the two diseases (Table 4).…”

Section: Review Of Previous Meta-analysismentioning

confidence: 99%

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The Role of Genetic Polymorphisms in High-Dose Methotrexate Toxicity and Response in Hematological Malignancies: A Systematic Review and Meta-Analysis

Song

Liu

et al. 2021

Front. Pharmacol.

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Objective: High-dose methotrexate (HDMTX) is a mainstay therapeutic agent for the treatment of diverse hematological malignancies, and it plays a significant role in interindividual variability regarding the pharmacokinetics and toxicity. The genetic association of HDMTX has been widely investigated, but the conflicting results have complicated the clinical utility. Therefore, this systematic review aims to determine the role of gene variants within the HDMTX pathway and to fill the gap between knowledge and clinical practice.Methods: Databases including EMBASE, PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), and the Clinical Trials.gov were searched from inception to November 2020. We included twelve single-nucleotide polymorphisms (SNPs) within the HDMTX pathway, involving RFC1, SLCO1B1, ABCB1, FPGS, GGH, MTHFR, DHFR, TYMS, and ATIC. Meta-analysis was conducted by using Cochrane Collaboration Review Manager software 5.3. The odds ratios (ORs) or hazard ratios (HRs) with 95% confidence interval (95% CI) were analyzed to evaluate the associations between SNPs and clinical outcomes. This study was performed according to the PRISMA guideline.Results: In total, 34 studies with 4102 subjects were identified for the association analysis. Nine SNPs involving MTHFR, RFC1, ABCB1, SLCO1B1, TYMS, FPGS, and ATIC genes were investigated, while none of studies reported the polymorphisms of GGH and DHFR yet. Two SNPs were statistically associated with the increased risk of HDMTX toxicity: MTHFR 677C>T and hepatotoxicity (dominant, OR=1.52, 95% CI=1.03-2.23; recessive, OR=1.68, 95% CI=1.10–2.55; allelic, OR=1.41, 95% CI=1.01–1.97), mucositis (dominant, OR=2.11, 95% CI=1.31–3.41; allelic, OR=1.91, 95% CI=1.28–2.85), and renal toxicity (recessive, OR=3.54, 95% CI=1.81–6.90; allelic, OR=1.89, 95% CI=1.18–3.02); ABCB1 3435C>T and hepatotoxicity (dominant, OR=3.80, 95% CI=1.68-8.61), whereas a tendency toward the decreased risk of HDMTX toxicity was present in three SNPs: TYMS 2R>3R and mucositis (dominant, OR=0.66, 95% CI=0.47–0.94); RFC1 80A>G and hepatotoxicity (recessive, OR=0.35, 95% CI=0.16–0.76); and MTHFR 1298A>C and renal toxicity (allelic, OR=0.41, 95% CI=0.18–0.97). Since the data of prognosis outcomes was substantially lacking, current studies were underpowered to investigate the genetic association.Conclusions: We conclude that genotyping of MTHFR and/or ABCB1 polymorphisms prior to treatment, MTHFR 677C>T particularly, is likely to be potentially useful with the aim of tailoring HDMTX therapy and thus reducing toxicity in patients with hematological malignancies.

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Section: General Findings and Trendssupporting

confidence: 91%

Section: Review Of Previous Meta-analysismentioning

confidence: 99%

The Role of Genetic Polymorphisms in High-Dose Methotrexate Toxicity and Response in Hematological Malignancies: A Systematic Review and Meta-Analysis

Song

Liu

et al. 2021

Front. Pharmacol.

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“…The findings suggested that grade 3-4 liver toxicity was significantly associated with rs1801133 polymorphism under various contrasts in the Asian population but not in the overall population, indicating the influence of ethnicity on the toxicity-polymorphism association. Previous studies have shown the inconsistences of MTX-related toxicities in populations from different ethnicities ( 37 ). Meanwhile, a significant association was also noticed between grade 3-4 mucositis and MTHFR rs1801133 polymorphism.…”

Section: Discussionmentioning

confidence: 99%

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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“…В этой же работе не обнаружено связи между концентрацией МТХ в плазме и развитием мукозита. В дальнейшем проведенный метаанализ показал, что полиморфизм MTRR c.66A>G ассоциирован с развитием мукозита у пациентов, получавших терапию MTX [39].…”

Section: фармакогенетические предикторы токсичностиunclassified

Role of pharmacogenetic factors in the development of side effects of methotrexate in the treatment of malignant tumors: A review

et al. 2021

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Methotrexate (MTX) is one of the main chemotherapeutic agents that has determined the high effectiveness of protocols for the treatment of acute lymphoblastic leukemia and non-Hodgkin lymphomas. The reverse side of the high anti-tumor activity of MTX is the adverse reactions, which require accompanying preventive therapy. But even modern accompanying therapy in some cases does not avoid severe toxicity from the skin and mucous membranes, nervous system, kidneys, liver. MTX pharmacokinetics exhibits significant individual variability, which may be a reflection of genetic variability. Numerous pharmacogenetic studies have evaluated the effect of polymorphism of various genes involved in MTX metabolism on MTX pharmacokinetics and the development of toxic manifestations in order to improve patient outcomes and decrease drug toxicity. This review presents impact of key metabolic MTX genes (ATIC, DHFR, GGH, FPGS, MTHFR, MTR, MTRR, TYMS) and transporter proteins genes (ABCB1, ABCG2, ABCC2, ABCC4, SLC19A1, SLCO1B1) in the development of MTX side effects. Polymorphic markers in SLCO1B1 gene have the most influence with MTX pharmacokinetic.

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Genetic variants associated with methotrexate-induced mucositis in cancer treatment: A systematic review and meta-analysis

Cited by 14 publications

References 74 publications

The Role of Genetic Polymorphisms in High-Dose Methotrexate Toxicity and Response in Hematological Malignancies: A Systematic Review and Meta-Analysis

The Role of Genetic Polymorphisms in High-Dose Methotrexate Toxicity and Response in Hematological Malignancies: A Systematic Review and Meta-Analysis

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

Role of pharmacogenetic factors in the development of side effects of methotrexate in the treatment of malignant tumors: A review

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