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

Author

Iris Elens, Sabine Deprez, Thibo Billiet, Charlotte Sleurs, Veerle Labarque, Anne Uyttebroeck, Stefaan Van Gool, Jurgen Lemiere, and Rudi D'Hooge

Subjects
Medicine, Science
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.

Published
2021
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2. Methylene tetrahydrofolate reductase A1298C polymorphisms influence the adult sequelae of chemotherapy in childhood-leukemia survivors

Author

Anne Uyttebroeck, Charlotte Sleurs, Rudi D'Hooge, Jurgen Lemiere, Stefaan Van Gool, Sabine Deprez, Iris Elens, Veerle Labarque, and Thibo Billiet

Subjects
Central Nervous System, Male, Heredity, Physiology, medicine.medical_treatment, Cancer Treatment, Toxicology, Pathology and Laboratory Medicine, Nervous System, Biochemistry, Homozygosity, Diagnostic Radiology, chemistry.chemical_compound, Cerebrospinal fluid, Cognition, Cancer Survivors, Medicine and Health Sciences, Child, Cerebrospinal Fluid, Intelligence Tests, Multidisciplinary, biology, Radiology and Imaging, Drugs, Brain, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Magnetic Resonance Imaging, Body Fluids, Oncology, Child, Preschool, Antifolate, Disease Progression, Medicine, Female, Anatomy, medicine.drug, Research Article, Adult, medicine.medical_specialty, Childhood leukemia, Adolescent, Drug-Related Side Effects and Adverse Reactions, Genotype, Imaging Techniques, Science, Rest, tau Proteins, Neuropathology, Research and Analysis Methods, Polymorphism, Single Nucleotide, Folinic acid, Young Adult, Drug Therapy, Diagnostic Medicine, Internal medicine, medicine, Genetics, Humans, Methylenetetrahydrofolate Reductase (NADPH2), Retrospective Studies, Pharmacology, Chemotherapy, Toxicity, business.industry, Biology and Life Sciences, medicine.disease, Endocrinology, Methotrexate, Diffusion Magnetic Resonance Imaging, chemistry, Methylenetetrahydrofolate reductase, biology.protein, Folic Acid Antagonists, business, Biomarkers
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. ispartof: Plos One vol:16 issue:4 pages:1-13 ispartof: location:United States status: published

Published
2021

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