Polymorphisms of genes controlling homocysteine levels and IQ score following the treatment for childhood ALL.
BACKGROUND
One of the causes of long-term morbidity associated with the treatment of acute lymphoblastic leukemia (ALL) is late neurotoxicity manifesting as impairment of higher cognitive functions. Cranial radiation therapy (CRT) and chemotherapeutic agents, particularly methotrexate (MTX), are often suggested to be major contributing factors for its development. Homocysteinemia that arises as a result of MTX-induced folate depletion was proposed to play a role in MTX-related neurotoxicity. Several enzymes are essential to maintain the homocysteine levels. Their different functional forms, associated with common genetic polymorphisms, may modulate homocysteine levels and thereby influence MTX-associated neurotoxicity.


OBJECTIVE
To test this hypothesis we assessed whether the variants of the methylene tetrahydrofolate reductase (MTHFR), methionine synthase (MTR), methionine synthase reductase (MTRR), cystathionine beta-synthase (CBS) and endothelial nitric acid synthase (eNOS, NOS3) genes, acting either independently or in conjunction with other risk factors, influenced the cognitive functioning in ALL patients. The influence of the genes was measured by estimating the change in IQ scores over a period of 4 years post ALL diagnosis.


RESULTS
Two variants, the CBS 844ins68 polymorphism and NOS3 894T homozygosity, were associated with a change in IQ scores (p = 0.01 and 0.007, respectively). A multivariate model obtained through step-wise selection pointed to the importance of the NOS3 894TT genotype only. This effect appears to be dependent on CRT; IQ decline was apparent among individuals with the 894TT genotype who received radiation therapy (p = 0.03). Furthermore, additional factors affecting IQ were identified, including the treatment administered (i.e., CRT; p = 0.02) and a younger age at diagnosis (p = 0.003), and the modifying effect of the treatment protocols was also noted (p = 0.04).


CONCLUSIONS
The results suggest that NOS3 genotyping might identify individuals that are susceptible to intellectual impairment following ALL treatment.
Krajinovic
Maja
M
Hôpital Sainte-Justine, Service d'Hématologie-Oncologie, Centre de Recherche, 3175 Côte Sainte-Catherine, Montréal, Québec H3T 1C5, Canada. maja.krajinovic@umontreal.ca
Robaey
Philippe
P
Chiasson
Sonia
S
Lemieux-Blanchard
Emilie
E
Rouillard
Mélanie
M
Primeau
Melanie
M
Bournissen
Facundo Garcia
FG
Moghrabi
Albert
A
D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / Q000235:genetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy; D003541:Cystathionine beta-Synthase / Q000235:genetics; D005287:Ferredoxin-NADP Reductase / Q000235:genetics; D005500:Follow-Up Studies; D014644:Genetic Variation; D006710:Homocysteine / Q000097:blood / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007223:Infant; D007361:Intelligence Tests; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D008954:Models, Biological; D052250:Nitric Oxide Synthase Type III / Q000235:genetics*; D011110:Polymorphism, Genetic; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis / Q000188:drug therapy* / Q000532:radiotherapy*; D013997:Time Factors
D006710:Homocysteine; D052250:Nitric Oxide Synthase Type III; C111241:methionine synthase reductase; D005287:Ferredoxin-NADP Reductase; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; D003541:Cystathionine beta-Synthase