The Role of Single Nucleotide Polymorphisms in Transporter Proteins and the Folate Metabolism Pathway in Delayed Methotrexate Excretion: A Case Report and Literature Review

Figures & data

Figure 1 Time course of plasma methotrexate concentrations (A) and medications and liver/renal function (B).

Table 1 Genotype of the Targeted SNPs

Gene	rs No.	SNP	Genotype
SLCO1B1	rs4149056	TT	wt
	rs11045879	CT	het
SLC19A1	rs1051296	AC	het
ABCB1	rs1045642	AG	het
	rs2032582	AC	het
	rs1128503	AA	wt
ABCC2	rs717620	CC	wt
MTHFR	rs1801133	CT	het
	rs1801131	TT	wt

Note: The SNPs in bold type indicate mutations.

Abbreviations: wt, homozygous wild-type genotype; het, heterozygous variant genotype.

Table 2 Pharmacogenetic Literatures Information of HD-MTX in OS

First Author and Year	Study Population	Principal Findings	References
Lui G, (2018)	OS2006 trial (a French multicentre, open-label, parallel group, Phase III, randomized controlled trial)	Rs13120400, rs13137622 and rs12505410 on ABCG2 gene and rs4148324 in UGT1A gene were significantly associated with MTX-PK CL.	[7]
Hegyi M, (2017)	59 children Hungarian diagnosed with OS	The SNPs ABCB1 rs928256, ABCC3 rs4793665, GGH rs3758149, and NR1I2 rs3814058 SNPs were associated with MTX-PK parameters.	[15]
Lambrecht L, (2017)	48 Belgium patients of new diagnoses with OS <18 years	The MTHFR C667T (rs18011330) polymorphism is associated with toxicity or overall survival, but could be used for relapse risk stratification	[17]
Claudia M, (2016)	196 patients with newly diagnosed HGOS in Italy	Genotypes of ABCC2 (rs2273697), GH (rs11545078), TP53 (rs1642785), CYP2B6*6 (rs3745274 and rs2279343) were associated with EFS. Genotypes of ABCB1 (rs1128503), ABCC2 (rs2273697), ABCC2 (rs3740066), ERCC1 (rs3212986), XPD (rs1799793), XRCC3 (rs861539), MTHFR (rs1801131) and GGH (rs1800909) were associated with elevated risk for toxicity development.	[18]
S Jabeen, (2015)	62 HDMTX-treated OS patients at The Norwegian Radium Hospital	RFC1 (rs1051266) had significantly better survival and a lower frequency of metastasis. Rs1053129 in the dihydrofolate reductase (DHFR) gene were more likely to have a metastasis.	[19]
Goričar K, (2014)	118 OS patients were diagnosed in Slovenia	Polymorphic SLCO1B1 rs4149056 and rs11045879 alleles were associated with significantly higher serum methotrexate area under the curve.	[16]
MM Hagleitner (2014)	115 Dutch paediatric oncology patients. These include 63 newly diagnosed, high-grade OS patients and 52 patients with denovo acute lymphoblastic leukaemia (ALL).	The MTHFR 677T allele (rs1801133) has only a minor role in the development of MTX-induced hepatotoxicity.	[20]
Rachael E, (2012)	60 patients who had completed MAP chemotherapy	ABCC2 (rs717620) and GSTP1 (rs1695) were associated with poor histological response, whereas MTHFD1 (rs2236225) was protective. Methotrexate toxicity was increased in variants of MTHFR (rs1801131), ABCB1 (rs1045642), and ABCC2 (rs17222723). Variants of GSTP1 (rs1695) were at increased risk of myelosuppression and cardiac damage.	[21]
Caronia D, (2011)	102 consecutive patients diagnosed with OS at the University Clinic of Navarra, Pamplona, Spain	Rs4148416 in ABCC3, and three SNPs in ABCB1, rs4148737, rs1128503 and rs10276036 were associated with overall survival.	[24]
Ana Patino-Garci, (2009)	96 children and adolescents with osteosarcoma	MTHFR rs1801133 and MTR rs1805087 were associated with haematologic and gastrointestinal toxicity.	[22]
Judit Muller, (2008)	A 10-year-old boy with OSC	The authors hypothesize that MTX toxicity was associated between homozygosity of the MTHFR rs1801133 polymorphism.	[23]

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