Association between SLC19A1 gene polymorphism and high dose methotrexate toxicity in childhood acute lymphoblastic leukaemia and non Hodgkin malignant lymphoma: introducing a haplotype based approach

Characteristic	ALL patients
Characteristic	(N = 88)
Gender (%)
Male	41 (46.6)
Female	47 (53.4)
Median age at diagnosis, years (range)	4.58 (0.3–16.6)
Median body surface area, m² (range)	0.73 (0.4–1.9)
Leukaemia subtype (%);
B-cell	72 (81.8)
T-cell	13 (14.7)
Undetermined	3 (3.4)
Median No. leukocytes at diagnosis, 10⁹ cells/L (range)	9.35 (1–1650)
Median No. thrombocytes at diagnosis, 10⁹ cells/L (range)	72 (3–553)
Median haemoglobin conc., g/l (range)	84 (43–148)
Median % of blasts at diagnosis (range)	23.5 (0–97)
Median MTX dose, mg (range)	3300 (540–9200)
MTX response	Present, N (%)
MTX response
Relapse	8 (9.2)**
Exitus	4 (4.6)**
All MTX-induced ADEs*	48 (54.5)
Leukopenia	33 (37.5)
Thrombocytopenia	16 (18.2)
Mucositis	15 (17.0)
Neurotoxicity	7 (8.0)**

** data is missing for one patient

* data was collected after the first cycle of MTX

** data is missing for one patient

Table 2

The influence of rs2838958 genotype on mucositis development - univariate logistic regression analysis

Degree of moscositis	rs2838958 genotype		OR(95%CI)	P

	TT (%)	TC + CC (%)
0	18 (66.7)	53 (89.8)	reference
1	4 (14.8)	4 (6.8)	0.340 (0.077–1.500)	0.154
2	4 (14.8)	2 (3.4)	0.170 (0.029–1.007)	0.051
4	1 (3.7)	0 (0.0)	-*
1–4	9 (33.3)	6 (10.2)	0.226 (0.071–0.725)	0.009
Mean value ± STD	0.59	0.14		0.007

* Calculation was not possible

Table 3

The impact of SLC19A1 genotypes on the occurrence of any and specific MTX-induced adverse events using multivariate analysis – an additive model

SNP ID	Any adverse events		Leukopenia		Thrombocytopenia		Mucositis		Neurotoxicity

	OR	P	OR	P	OR	P	OR	P	OR	P
	(CI 95%)	P	(CI 95%)	P	(CI 95%)	P	(CI 95%)	P	(CI 95%)	P
rs1131590	0.719	0.360	0.609	0.150	1.170	0.696	1.292	0.579	0.542	0.361
rs1131590	(0.354–1.458)	0.360	(0.310–1.197)	0.150	(0.532–2.576)	0.696	(0.525–3.170)	0.579	(0.146–2.016)	0.361
rs1051200	1.392	0.360	1.643	0.150	0.855	0.696	0.775	0.579	0.542	0.361
rs1051200	(0.686–2.824)	0.360	(0.836–3.230)	0.150	(0.388–1.881)	0.696	(0.316–1.906)	0.579	(0.146–2.016)	0.361
rs2838958	1.221	0.583	1.684	0.136	0.556	0.172	0.476	0.130	0.453	0.236
rs2838958	(0.599–2.490)	0.583	(0.849–3.339)	0.136	(0.240–1.291)	0.172	(0.182–1.243)	0.130	(0.122–1.677)	0.236
rs2838956	1.411	0.349	1.742	0.113	0.689	0.374	0.705	0.454	0.596	0.434
rs2838956	(0.686–2.899)	0.349	(0.878–3.458)	0.113	(0.303–1.566)	0.374	(0.283–1.759)	0.454	(0.163–2.182)	0.434
rs17004785	0.849	0.772	1.393	0.545	0.854	0.821	0.672	0.606	1.226	0.800
rs17004785	(0.280–2.572)	0.772	(0.476–4.079)	0.545	(0.218–3.349)	0.821	(0.148–3.055)	0.606	(0.255–5.899)	0.800
rs12483377	1.475	0.478	1.825	0.238	1.688	0.368	0.930	0.914	1.061	0.939
rs12483377	(0.504–4.318)	0.478	(0.672–4.956)	0.238	(0.540–5.280)	0.368	(0.249–3.473)	0.914	(0.232–4.861)	0.939
rs2838951	1.261	0.483	0.740	0.351	1.652	0.185	2.160	0.081	1.693	0.337
rs2838951	(0.666–2.412)	0.483	(0.392–1.394)	0.351	(0.786–3.473)	0.185	(0.909–5.129)	0.081	(0.577–4.967)	0.337

The estimates for the odds ratio (OR) were adjusted to the following variables: age, sex, and treatment regimen.

Graphic presentation of haploblocks and selected SNPs in *SLC19A1*.

Table 4

SLC19A1 haplotype frequencies in patients with ALL and NHML

Haplotype*	Frequency	Standard error
H1 = CACCCCG	0.396	0.037
H2 = TGTTCCC	0.334	0.036
H3 = TGTTGTC	0.094	0.022
H4 = TGTTCCG	0.053	0.017
H5 = CATTCCC	0.017	0.010
Other	0.106

* SNP rs1131596, rs1051266, rs2838958, rs2838956, rs17004785, rs12483377, rs2838951 from 5’ to 3’, respectively

Table 5

The impact of gender, age, treatment regimen and SLC19A1 haplotypes on the occurrence of any and specific (thrombocytopenia, mucositis, and neurotoxicity) MTX-induced adverse events

	All		Thrombocytopenia		Mucositis		Neurotoxicity

	OR (95% CI)	P	OR (95% CI)	P	OR (95% CI)	P	OR (95% CI)	P
Gender	2.385	0.078	1.615	0.413	1.523	0.520	0.531	0.475
Gender	(0.908–6.259)	0.078	(5.134–5.076)	0.413	(0.423–5.472)	0.520	(0.093–3.024)	0.475
Age	1.028	0.588	9.526	0.440	1.054	0.396	1.088	0.289
Age	(0.931–1.134)	0.588	(8.422–1.078)	0.440	(0.935–1.190)	0.396	(0.931–1.272)	0.289
Treatment regimen	2.050	0.031*	9.839	0.962	1.676	0.255	1.282	0.678
Treatment regimen	(1.065–3.943)	0.031*	(4.620–2.095)	0.962	(0.689–4.075)	0.255	(0.397–4.139)	0.678
H1 = CACCCCG	1.000	0.943	6.615	0.352	0.419	0.096	0.309	0.120
H1 = CACCCCG	(0.472–2.117)	0.943	(2.769–1.579)	0.352	(0.150–1.167)	0.096	(0.070–1.364)	0.120
H3 = TGTTGTC	1.110	0.844	9.220	0.891	0.593	0.515	0.951	0.934
H3 = TGTTGTC	(0.335–3.618)	0.844	(2.254–3.750)	0.891	(0.122–2.877)	0.515	(0.175–5.150)	0.934
H4 = TGTTCCC	0.143	0.030*	3.617	0.379	0.005	0.985	0.014	0.992
H4 = TGTTCCC	(0.023–0.852)	0.030*	(4.568–2.541)	0.379	(0.0–NC)	0.985	(0.0–NC)	0.992
Rare haplotypes	2.002	0.275	9.113	0.871	2.002	0.275	2.002	0.275
Rare haplotypes	(0.580–6.775)	0.275	(2.607–3.171)	0.871	(0.580–6.775)	0.275	(0.580–6.775)	0.275

* p < 0.05; H2 was the reference haplotype

Articles in this issue

DOI: https://doi.org/10.1515/raon-2017-0040 | Journal eISSN: 1581-3207 | Journal ISSN: 1318-2099

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Language: English

Page range: 455 - 462

Submitted on: Feb 14, 2017

Accepted on: Aug 18, 2017

Published on: Sep 18, 2017

Published by: Association of Radiology and Oncology

In partnership with: Paradigm Publishing Services

Publication frequency: 4 issues per year

Keywords:

acute lymphoblastic leukaemia,

genetic polymorphism,

Related subjects:

© 2017 Barbara Faganel Kotnik, Janez Jazbec, Petra Bohanec Grabar, Cristina Rodriguez-Antona, Vita Dolzan, published by Association of Radiology and Oncology
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

Volume 51 (2017): Issue 4 (December 2017)

Association between SLC19A1 gene polymorphism and high dose methotrexate toxicity in childhood acute lymphoblastic leukaemia and non Hodgkin malignant lymphoma: introducing a haplotype based approach

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Table 1

Table 2

Table 3

Figure 1

Table 4

Table 5

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