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

PLoS One. 2021 Apr 30;16(4):e0250228. doi: 10.1371/journal.pone.0250228. eCollection 2021.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Brain / pathology
  • Cancer Survivors
  • Child
  • Child, Preschool
  • Cognition / drug effects*
  • Diffusion Magnetic Resonance Imaging / methods
  • Disease Progression
  • Drug Therapy / methods
  • Drug-Related Side Effects and Adverse Reactions / genetics
  • Female
  • Folic Acid Antagonists / therapeutic use
  • Genotype
  • Humans
  • Intelligence Tests
  • Magnetic Resonance Imaging / methods
  • Male
  • Methotrexate / therapeutic use
  • Methylenetetrahydrofolate Reductase (NADPH2) / genetics*
  • Methylenetetrahydrofolate Reductase (NADPH2) / metabolism
  • Polymorphism, Single Nucleotide / genetics
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Rest / physiology
  • Retrospective Studies
  • Young Adult
  • tau Proteins / analysis
  • tau Proteins / cerebrospinal fluid

Substances

  • Folic Acid Antagonists
  • tau Proteins
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • Methotrexate

Grants and funding

This study was supported by the charity-based Olivia Hendrickx Research Fund (www.olivia.be) in the form of funding awarded to IE, the University of Leuven, and Leuven University Hospital. Icometrix provided support in the form of a salary for TB. The specific roles of this author are articulated in the ‘author contributions’ section. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.