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Methotrexate neurotoxicity: risk factors & outcome
Six relapses occurred among children who had IT MTX permanently ceased following MTX neurotoxicity (n=48), and five of 48 were CNS-based relapses (10.4%). In 34 patients where IT MTX was continued following MTX
neurotoxicity, there was one isolated CNS relapse (2.9%). Cumulative incidence of CNS relapse was increased in children where IT MTX was omitted permanently follow- ing symptomatic MTX neurotoxicity (n=48) compared to
Table 3. Top single-nucleotide polymorphisms for methotrexate neurotoxicity with significance levels P<1x10-6.
CHR Position SNP Non Effect effect allele
allele
6 20196934 rs4712462 A G
19 14590919 rs2241357 G A
3 195925355 rs1106479 C T
17 747700 rs35307996 GC G
MAF P
0.35 2.54E-07
0.2 3.60E-07
0.16 4.08E-07
0.2 5.70E-07
0.23 6.19E-07
0.18 7.50E-07
0.11 9.73E-07
OR OR 95% CI OR 95% CI (lower) (upper)
Genea
MBOAT1
GIPC1
Location
intron
intron
Gene function
Involved in fatty acid
biomembrane synthesis.
Possible role in neuronal
growth and differentiation.
siRNA-mediated knockdown
of MBOAT1 leads to reduced neurite growth26
Encodes for GIPC1,
a scaffolding protein that regulates cell surface receptor dynamics in endothelial cells. Microdeletionsat this locus (19p13.12) have been reported25 Involvedin post-translational protein modification that alters trafficking, activity and localization of lipidated proteins, such as R-Ras29 Encoded protein acts
as a redox-dependent regulator of the Wnt signaling pathway, exerting effects via dishevelled (dvl), and
is involved in cell growth and differentiation27 Located at 19p13.12. Encodes a protein that is involved in neuronal function and neuroprotection. siRNA-mediated knockdown of PKN1 led to neuron apoptosis and inhibition of neurite formation28 HMGB1 family of
genes contain an HMG-box domain that bends DNA, affects transcription and facilitates DNA-protein
interactions50
19
9
14571966 rs74956940
124286453 rs62576054
C G
G C
0.26 0.16 0.45
4.18 2.41 7.24
3.97 2.33 6.75
0.11 0.03 0.34
3.58 2.17 5.92
16.7 3.92 71.13
5.24 2.73 10.07
ZDHHC19 intronb
NXN intron
PKN1 intron
HMGB1P37 unknown
- -
13 95072136 rs9590003 G A
This table shows the top seven single-nucleotide polymorphisms (SNP) that associate with methotrexate (MTX) central neurotoxicity at significance level P<1x10-6, ordered by P-value for significance. SNP with a minor allele frequency (MAF) <1% were excluded. aThe annotated gene was determined by cross-referencing relevant genomic databases (see the Online Supplementary Appendix). bintron (downstream variant/nc transcript variant). SNP with a minor allele frequency (MAF) <1% were excluded. Odds ratio (OR) 95% Confidence Interval (CI) (lower) and OR 95% CI (upper) refer to lower value and upper value for 95% CI for odds ratio. P-value from genome wide association study,where P<5x10-6 is significant. CHR: chromosome; siRNA: small interfering RNA.
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