Polymorphisms of Genes Controlling Homocysteine Levels and IQ Score Following the Treatment for Childhood ALL

Abstract

The results suggest that NOS3 genotyping might identify individuals that are susceptible to intellectual impairment following ALL treatment.

Clinical Patterns and Biological Correlates of Cognitive Dysfunction Associated with Cancer Therapy

“…Polymorphisms that alter the pharmacodynamics of chemotherapeutic agents may place certain individuals at greater risk through greater exposure to potentially toxic agents secondary to less detoxification and/or greater permeability of agents across the blood-brain barrier [31][32][33]. For instance, polymorphisms modulating the folic acid pathway have been associated with diminished intelligence in children with leukemia treated with methotrexate [34]. The relationships between polymorphisms in genes responsible for various repair processes (e.g., apolipoprotein E) and the development of cognitive dysfunction are increasingly recognized [35,36].…”

Common Polymorphisms in Angiogenesis

“…In ALL the amino acid polymorphism can affect a patient's IQ following cranial radiation (Krajinovic et al 2005). Similarly, in the breast cancer setting, a reduced incidence of radiation-induced telangiectasias was noted in women with lower-activity NOS3 genotypes (Kuptsova et al 2008).…”

Pharmacogenetics of the neurodevelopmental impact of anticancer chemotherapy

“…In children treated for acute lymphoblastic leukemia, the effects of different polymorphisms (MTHR C677T, MTHFR A1298C, MTR A2756G, MTRR A66G, NOS3 G894T, NOS T-786C, and CBS 844ins68) were tested on changes in IQ scores over a period of 4 years postdiagnosis [Krajinovic et al, 2005]. Two variants, the CBS 844ins68 and the homozygotes NOS3 G894T were associated with changes in IQ scores 2 years after diagnosis.…”

“…Following this approach for long-term neurodevelopmental toxicity, a pharmacogenetic model could lead to a more personalized treatment through identification of significant genes, integration of multiple genes into a genetic profile, and use of the profile to improve outcome in practice. Presently, the field is nascent, as there is only one publication that shows increased susceptibility for adverse neurodevelopmental outcome following treatment of acute lymphoblastic leukemia of children with specific gene variants [Krajinovic et al, 2005]. We will thus focus on methotrexate (MTX), the drug most often implicated in neurotoxicity, which is a mainstay in the treatment of cancer and especially in the treatment of acute lymphoblastic leukemia.…”