Methylene tetrahydrofolate reductase A1298C polymorphisms influence the adult sequelae of chemotherapy in childhood-leukemia survivors.

Iris Elens,Veerle Labarque,Stefaan Van Gool,Thibo Billiet,Charlotte Sleurs,Jurgen Lemiere,Anne Uyttebroeck,Rudi D’Hooge,Sabine Deprez,Roland A. Ammann

doi:10.1371/journal.pone.0250228

Iris Elens, Veerle Labarque + Show 8 more

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https://doi.org/10.1371/journal.pone.0250228

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Abstract

This retrospective correlation study investigated the putative link between methylene tetrahydrofolate reductase (MTHFR) A1298C mutations and chemotherapy-related brain function changes in adult childhood-leukemia survivors. To this end, we determined the relationship between the particular MTHFR1298 genotype (AA, AC or CC) of 31 adult childhood-leukemia survivors, and (1) their CSF Tau and phosphorylated Tau (pTau) levels at the time of treatment, (2) their adult performance intelligence quotient (PIQ), and (3) their regional brain connectivity using diffusion magnetic resonance imaging (dMRI) and resting-state functional MRI (rsfMRI). We confirmed that neuropathology markers Tau and pTau significantly increased in CSF of children after intrathecal methotrexate administration. Highest concentrations of these toxicity markers were found during the induction phase of the therapy. Moreover, CSF concentrations of Tau and pTau during treatment were influenced by the children's particular MTHFR1298 genotype. CSF Tau (but not pTau) levels significantly dropped after folinic acid supplementation. At adult age (on average 13.1 years since the end of their treatment), their particular MTHFR1298 genotype (AA, AC or CC) influenced the changes in PIQ and cortical connectivity that we found to be related to their childhood exposure to chemotherapeutics. In summary, we suggest that homozygous MTHFR1298CC individuals are more vulnerable to the adult sequelae of antifolate chemotherapy.

Highlights

Acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL) account for one third of pediatric malignancies
These structural changes coincided with hypoconnectivity between the inferior temporal gyrus (ITG), and the default mode network (DMN) that is involved in executive functioning [8,9]
Levels of phosphorylated Tau (pTau) were different between “LP1” and “LP2-5”, between “LP2-5” and “LP6-10”, and between “LP6-10” and “LP11-15”. Both CSF Tau and pTau increased after the first intrathecal methotrexate administration, LP1 versus LP2

Summary

Introduction

Acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL) account for one third of pediatric malignancies. Using diffusion tensor imaging (DTI), we previously demonstrated higher fractional anisotropy (FA) and lower orientation dispersion index (ODI) in the left centrum semiovale of childhood-leukemia survivors These structural changes coincided with hypoconnectivity between the inferior temporal gyrus (ITG), and the default mode network (DMN) that is involved in executive functioning [8,9]. We hypothesize that the MTHFR1298 genotype of former patients (AA, AC or CC) might influence some of the previously identified outcomes, shown to be vulnerable to methotrexate exposure, such as (1) Tau and pTau CSF levels during treatment [14,16], (2) adult performance intelligence quotient (PIQ), and (3) functional and structural MRI measures, such as FA and ODI in the left centrum semiovale and resting state functional connectivity (RSFC) between the default mode network (DMN) and the inferior temporal gyrus (ITG) [24]

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