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01-03-2022 | Acute Lymphoblastic Leukemia | Original Article

Evaluation of cytogenetic and molecular markers with MTX-mediated toxicity in pediatric acute lymphoblastic leukemia patients

Authors: Ravi Ramalingam, Harpreet Kaur, Julius Xavier Scott, Latha M. Sneha, Ganeshprasad Arunkumar, Arathi Srinivasan, Solomon F. D. Paul

Published in: Cancer Chemotherapy and Pharmacology | Issue 3/2022

Abstract

Purpose

Pediatric acute lymphoblastic leukemia (pALL) patients have better overall survival and methotrexate (MTX) is an effective drug used in their treatment. However, the treatment-related adverse effects (TRAEs) have a bigger impact on the therapy. In this study, we have evaluated the association of polymorphisms in genes encoding proteins engaged in MTX metabolism, and the cytogenetic aberrations with TRAEs.

Methods

A total of 115 patients between the age of 1 and 18 years (average: 6.6) under maintenance therapy were selected for the study. SLC19A1 (c.80G > A), MTHFR (c.677C > T; c.1298A > C), and TYMS (c.*450_*455del) genotypes were determined using PCR techniques and Sanger sequencing. Cytogenetic and SNP findings were analyzed for any association with the reported toxicities using odds ratio, chi-square test, multifactor dimensionality reduction (MDR) analysis for synergistic effect and, multinomial logistic regression analysis for the likelihood of adverse events.

Results

Among the evaluated genetic variations, SLC19A1 (c.80G > A) was significantly associated with TRAEs (OR = 5.71, p = 0.002). Multinomial logistic regression analysis (chi-sq = 16.64, p < 0.001) and MDR analysis (chi-sq = 10.51 p < 0.001) confirmed the finding. On the other hand, no significant association was observed between adverse events and any specific cytogenetic aberration.

Conclusion

SLC19A1 facilitates the import of cyclic dinucleotides and reduced folates, evaluating genotypes in this gene can help in better management of patients on methotrexate treatment. Assessing a broader gene panel can help in finding more associated markers and delivering personalized medicine to the patients.

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Longo DL, Hunger SP, Mullighan CG (2015) Acute lymphoblastic leukemia in children. N Engl J Med 373(16):1541–1552. https://doi.org/10.1056/nejmra1400972CrossRef

Moon W, Loftus EV (2016) Review article: recent advances in pharmacogenetics and pharmacokinetics for safe and effective thiopurine therapy in inflammatory bowel disease. Aliment Pharmacol Ther 43(8):863–883. https://doi.org/10.1111/apt.13559CrossRefPubMed

Rudin S, Marable M, Huang RS (2017) The promise of pharmacogenomics in reducing toxicity during acute lymphoblastic leukemia maintenance treatment. Genomics Proteomics Bioinformatics 15(2):82–93. https://doi.org/10.1016/j.gpb.2016.11.003CrossRefPubMedPubMedCentral

Fukino K, Kawashima T, Suzuki M et al (2007) Methylenetetrahydrofolate reductase and reduced folate carrier-1 genotypes and methotrexate serum concentrations in patients with rheumatoid arthritis. J Toxicol Sci 32(4):449–452. https://doi.org/10.2131/jts.32.449CrossRefPubMed

Laverdie C, Chiasson S, Costea I et al (2002) Brief report Polymorphism G 80 A in the reduced folate carrier gene and its relationship to methotrexate plasma levels and outcome of childhood acute lymphoblastic leukemia. Blood 100(10):3832–3834. https://doi.org/10.1182/blood.v100.10.3832CrossRef

Cwiklinska M, Czogala M, Kwiecinska K et al (2020) Polymorphisms of SLC19A1 80 G>A, MTHFR 677 C>T, and tandem TS repeats influence pharmacokinetics, acute liver toxicity, and vomiting in children with acute lymphoblastic leukemia treated with high doses of methotrexate. Front Pediatr. https://doi.org/10.3389/fped.2020.00307CrossRefPubMedPubMedCentral

Whetstine JR, Gifford AJ, Witt T, et al (2001) Single nucleotide polymorphisms in the human reduced folate carrier: characterization of a high-frequency G/A variant at position 80 and transport properties of the His27 and Arg27 carriers. Clin Cancer Res. 7(11):3416–3422. https://clincancerres.aacrjournals.org/content/7/11/3416.long

De Miranda DO, Barros JEXS, Vieira MMS et al (2014) Reduced folate carrier-1 G80a gene polymorphism is associated with neuroblastoma’s development. Mol Biol Rep 41(8):5069–5075. https://doi.org/10.1007/s11033-014-3372-6CrossRefPubMed

Motassem A, Rand Y, Daniah F et al (2019) Folate pathway genetic polymorphisms modulate methotrexate-induced toxicity in childhood acute lymphoblastic leukemia. Cancer Chemother Pharmacol 4:755–762. https://doi.org/10.1007/s00280-019-03776-8CrossRef

10.

Ulrich CM, Yasui Y, Storb R et al (2013) Pharmacogenetics of methotrexate : toxicity among marrow transplantation patients varies with the methylenetetrahydrofolate reductase C677T polymorphism Brief report Pharmacogenetics of methotrexate : toxicity among marrow transplantation patients varies. Blood. https://doi.org/10.1182/blood.v98.1.231CrossRef

11.

Karas-Kuzelicki N, Milek M, Mlinaric-Rascan I (2010) MTHFR and TYMS genotypes influence TPMT activity and its differential modulation in males and females. Clin Biochem 43(1–2):37–42. https://doi.org/10.1016/j.clinbiochem.2009.09.003CrossRefPubMed

12.

Lazic J, Tosic N, Dokmanovic L et al (2010) Clinical features of the most common fusion genes in childhood acute lymphoblastic leukemia. Med Oncol 27(2):449–453. https://doi.org/10.1007/s12032-009-9232-xCrossRefPubMed

13.

Akpek G, Zahurak ML, Piantadosi S et al (2001) Development of a prognostic model for grading chronic graft-versus-host disease. Blood 97(5):1219–1226. https://doi.org/10.1182/blood.v97.5.1219CrossRefPubMed

14.

Tamashiro MS, Aikawa NE, Campos LMA et al (2011) Discrimination of acute lymphoblastic leukemia from systemic-onset juvenile idiopathic arthritis at disease onset. Clinics (Sao Paulo) 66(10):1665–1669. https://doi.org/10.1590/s1807-59322011001000001CrossRef

15.

Moulik N, Kumar A, Agrawal S et al (2016) Effect of folate status and methylenetetrahydrofolate reductase genotypes on the complications and outcome of high dose methotrexate chemotherapy in north Indian children with acute lymphoblastic leukemia. Indian J Med Paediatr Oncol 37(2):85–89. https://doi.org/10.4103/0971-5851.180144CrossRefPubMedPubMedCentral

16.

Salazar J, Altes A, Del Rio E et al (2012) Methotrexate consolidation treatment according to pharmacogenetics of MTHFR ameliorates event-free survival in childhood acute lymphoblastic leukaemia. Pharmacogenomics J 12(5):379–385. https://doi.org/10.1038/tpj.2011.25CrossRefPubMed

17.

Yang L, Hu X, Xu L (2012) Impact of methylenetetrahydrofolate reductase (MTHFR) polymorphisms on methotrexate-induced toxicities in acute lymphoblastic leukemia: a meta-analysis. Tumor Biol 33(5):1445–1454. https://doi.org/10.1007/s13277-012-0395-2CrossRef

18.

Motsinger AA, Ritchie MD (2006) Multifactor dimensionality reduction: an analysis strategy for modelling and detecting gene-gene interactions in human genetics and pharmacogenomics studies. Hum Genomics 2(5):318–328. https://doi.org/10.1186/1479-7364-2-5-318CrossRefPubMedPubMedCentral

19.

Pui C-H, Evans WE (2006) Treatment of acute lymphoblastic leukemia. N Engl J Med 354(2):166–178. https://doi.org/10.1056/nejmra052603CrossRefPubMed

20.

Inaba H, Greaves M, Mullighan CG (2013) Acute lymphoblastic leukaemia. Lancet (London, England) 381(9881):1943–1955. https://doi.org/10.1016/s0140-6736(12)62187-4CrossRef

21.

Pui C, Relling M (2004) Acute lymphoblastic leukemia. N Engl J Med 15:1535–1548. https://doi.org/10.1056/nejmra023001CrossRef

22.

Schmiegelow K (2009) Advances in individual prediction of methotrexate toxicity: a review. Br J Haematol 146(5):489–503. https://doi.org/10.1111/j.1365-2141.2009.07765.xCrossRefPubMed

23.

Lima A, Bernardes M, Sousa H et al (2014) SLC19A1 80G allele as a biomarker of methotrexate-related gastrointestinal toxicity in Portuguese rheumatoid arthritis patients. Pharmacogenomics 15(6):807–820. https://doi.org/10.2217/pgs.13.244CrossRefPubMed

24.

Kotur N, Lazic J, Ristivojevic B et al (2020) Pharmacogenomic markers of methotrexate response in the consolidation phase of pediatric acute lymphoblastic leukemia treatment. Genes (Basel) 11(4):1–17. https://doi.org/10.3390/genes11040468CrossRef

25.

Shimasaki N, Mori T, Samejima H et al (2006) Effects of methylenetetrahydrofolate reductase and reduced folate carrier 1 polymorphisms on high-dose methotrexate-induced toxicities in children with acute lymphoblastic leukemia or lymphoma. J Pediatr Hematol Oncol 28(2):64–68. https://doi.org/10.1097/01.mph.0000198269.61948.90CrossRefPubMed

26.

Choi R, Sohn I, Kim MJ et al (2019) Pathway genes and metabolites in thiopurine therapy in Korean children with acute lymphoblastic leukaemia. Br J Clin Pharmacol 85(7):1585–1597. https://doi.org/10.1111/bcp.13943CrossRefPubMedPubMedCentral

27.

Park JA, Shin HY (2016) Influence of genetic polymorphisms in the folate pathway on toxicity after high-dose methotrexate treatment in pediatric osteosarcoma. Blood Res 51(1):50–57. https://doi.org/10.5045/br.2016.51.1.50CrossRefPubMedPubMedCentral

28.

Li X, Hu M, Li W et al (2016) The association between reduced folate carrier-1 gene 80G/A polymorphism and methotrexate efficacy or methotrexate related-toxicity in rheumatoid arthritis: a meta-analysis. Int Immunopharmacol 38:8–15. https://doi.org/10.1016/j.intimp.2016.05.012CrossRefPubMed

29.

Kotnik BF, Grabnar I (2011) Association of genetic polymorphism in the folate metabolic pathway with methotrexate pharmacokinetics and toxicity in childhood acute lymphoblastic leukaemia and malignant lymphoma. Eur J Clin Pharmacol 10:993–1006. https://doi.org/10.1007/s00228-011-1046-zCrossRef

30.

Hou Z, Ye J, Haska CL et al (2006) Transmembrane domains 4, 5, 7, 8, and 10 of the human reduced folate carrier are important structural or functional components of the transmembrane channel for folate substrates. J Biol Chem 281(44):33588–33596. https://doi.org/10.1074/jbc.m607049200CrossRefPubMed

31.

Wang Y, Zhao R, Russell RG et al (2001) Localization of the murine reduced folate carrier as assessed by immunohistochemical analysis. Biochimica et Biophysica Acta (BBA) - Biomembranes. 1513(1):49–54. https://doi.org/10.1016/s0005-2736(01)00340-6CrossRef

32.

Zhao R, Russell RG, Wang Y et al (2001) Rescue of embryonic lethality in reduced folate carrier-deficient mice by maternal folic acid supplementation reveals early neonatal failure of hematopoietic organs. J Biol Chem 276(13):10224–10228. https://doi.org/10.1074/jbc.c000905200CrossRefPubMed

33.

Mikkelsen TS, Thorn CF, Yang JJ et al (2011) PharmGKB summary: methotrexate pathway. Pharmacogenet Genomics 21(10):679–686. https://doi.org/10.1097/fpc.0b013e328343dd93CrossRefPubMedPubMedCentral

34.

Ramalingam R, Kaur H, Scott XS et al (2021) Pharmacogenetic evaluation of 6-mercaptopurine-mediated toxicity in pediatric acute lymphoblastic leukemia patients from a South Indian population. Pharmacogenomics 22(7):401–411. https://doi.org/10.2217/pgs-2020-0193CrossRefPubMed

35.

Levy AS, Sather HN, Steinherz PG et al (2003) Reduced folate carrier and dihydrofolate reductase expression in acute lymphocytic leukemia may predict outcome: A Children’s Cancer Group study. J Pediatr Hematol Oncol 25(9):688–695. https://doi.org/10.1097/00043426-200309000-00004CrossRefPubMed

36.

Suthandiram S, Gan G-G, Zain SM et al (2014) Effect of polymorphisms within methotrexate pathway genes on methotrexate toxicity and plasma levels in adults with hematological malignancies. Pharmacogenomics 15(11):1479–1494. https://doi.org/10.2217/pgs.14.97CrossRefPubMed

37.

Bohanec Grabar P, Leandro-García LJ, Inglada-Pérez L et al (2012) Genetic variation in the SLC19A1 gene and methotrexate toxicity in rheumatoid arthritis patients. Pharmacogenomics 13(14):1583–1594. https://doi.org/10.2217/pgs.12.150CrossRefPubMed

38.

Schaller L, Lauschke VM (2019) The genetic landscape of the human solute carrier (SLC) transporter superfamily. Hum Genet 138(11–12):1359–1377. https://doi.org/10.1007/s00439-019-02081-xCrossRefPubMedPubMedCentral

39.

Muralidharan N, Misra DP, Jain VK et al (2017) Effect of thymidylate synthase (TYMS) gene polymorphisms with methotrexate treatment outcome in south Indian Tamil patients with rheumatoid arthritis. Clin Rheumatol 36(6):1253–1259. https://doi.org/10.1007/s10067-017-3608-7CrossRefPubMed

40.

Dorababu P, Naushad SM, Linga VG et al (2012) Genetic variants of thiopurine and folate metabolic pathways determine 6-MP-mediated hematological toxicity in childhood ALL. Pharmacogenomics 13(9):1001–1008. https://doi.org/10.2217/pgs.12.70CrossRefPubMed

41.

Manche SK, Jangala M, Dudekula D et al (2018) Polymorphisms in folate metabolism genes are associated with susceptibility to presbycusis. Life Sci 196(January):77–83. https://doi.org/10.1016/j.lfs.2018.01.015CrossRefPubMed

42.

Tiwari D, Das CR, Bose PD et al (2017) Associative role of TYMS6bpdel polymorphism and resulting hyperhomocysteinemia in the pathogenesis of preterm delivery and associated complications: a study from Northeast India. Gene 627:129–136. https://doi.org/10.1016/j.gene.2017.06.023CrossRefPubMed

43.

EL-Khodary NM, EL-Haggar SM, Eid MA et al (2012) Study of the pharmacokinetic and pharmacogenetic contribution to the toxicity of high-dose methotrexate in children with acute lymphoblastic leukemia. Med Oncol 29(3):2053–2062. https://doi.org/10.1007/s12032-011-9997-6CrossRefPubMed

44.

Campalani E, Arenas M, Marinaki AM et al (2007) Polymorphisms in folate, pyrimidine, and purine metabolism are associated with efficacy and toxicity of methotrexate in psoriasis. J Invest Dermatol 127(8):1860–1867. https://doi.org/10.1038/sj.jid.5700808CrossRefPubMed

45.

Soszynska K, Mucha B, Debski R et al (2008) The application of conventional cytogenetics, FISH, and RT-PCR to detect genetic changes in 70 children with ALL. Ann Hematol 87(12):991–1002. https://doi.org/10.1007/s00277-008-0540-6CrossRefPubMed

46.

Ariffin H, Chen SP, Kwok CS et al (2007) Ethnic differences in the frequency of subtypes of childhood acute lymphoblastic leukemia: Results of the Malaysia-Singapore Leukemia Study Group. J Pediatr Hematol Oncol 29(1):27–31. https://doi.org/10.1097/mph.0b013e318030ac4cCrossRefPubMed

Title: Evaluation of cytogenetic and molecular markers with MTX-mediated toxicity in pediatric acute lymphoblastic leukemia patients
Authors: Ravi Ramalingam
Harpreet Kaur
Julius Xavier Scott
Latha M. Sneha
Ganeshprasad Arunkumar
Arathi Srinivasan
Solomon F. D. Paul
Publication date: 01-03-2022
Publisher: Springer Berlin Heidelberg
Keywords: Acute Lymphoblastic Leukemia
Methotrexate
Methotrexate
Published in: Cancer Chemotherapy and Pharmacology / Issue 3/2022
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-022-04405-7

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