INTRODUCTION: 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. OBJECTIVES: 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). CONCLUSION: The results suggest that NOS3 genotyping might identify individuals that are susceptible to intellectual impairment following ALL treatment.
INTRODUCTION: 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. OBJECTIVES: 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). CONCLUSION: The results suggest that NOS3 genotyping might identify individuals that are susceptible to intellectual impairment following ALL treatment.
Authors: Torben S Mikkelsen; Caroline F Thorn; Jun J Yang; Cornelia M Ulrich; Deborah French; Gianluigi Zaza; Henry M Dunnenberger; Sharon Marsh; Howard L McLeod; Kathy Giacomini; Mara L Becker; Roger Gaedigk; James Steven Leeder; Leo Kager; Mary V Relling; William Evans; Teri E Klein; Russ B Altman Journal: Pharmacogenet Genomics Date: 2011-10 Impact factor: 2.089
Authors: Deborah P Waber; Jennifer Turek Queally; Lori Catania; Philippe Robaey; Ivonne Romero; Heather Adams; Cheryl Alyman; Christine Jandet-Brunet; Stephen E Sallan; Lewis B Silverman Journal: Pediatr Blood Cancer Date: 2011-06-30 Impact factor: 3.167
Authors: Dana M Sepe; Thomas McWilliams; Jinbo Chen; Aaron Kershenbaum; Huaqing Zhao; Mei La; Meenakshi Devidas; Beverly Lange; Timothy R Rebbeck; Richard Aplenc Journal: Pediatr Blood Cancer Date: 2011-05-25 Impact factor: 3.167
Authors: Kala Y Kamdar; Kevin R Krull; Randa A El-Zein; Pim Brouwers; Brian S Potter; Lynnette L Harris; Suzanne Holm; Zoann Dreyer; Fernando Scaglia; Carol J Etzel; Melissa Bondy; M Fatih Okcu Journal: Pediatr Blood Cancer Date: 2011-05-25 Impact factor: 3.167
Authors: F Aminkeng; C J D Ross; S R Rassekh; L R Brunham; J Sistonen; M-P Dube; M Ibrahim; T B Nyambo; S A Omar; A Froment; J-M Bodo; S Tishkoff; B C Carleton; M R Hayden Journal: Pharmacogenomics J Date: 2013-04-16 Impact factor: 3.550