title: Genetic mediators of neurocognitive outcomes in survivors of childhood acute lymphoblastic leukemia.
abstract: OBJECTIVE
  Survivors of childhood acute lymphoblastic leukemia (ALL) are at increased risk for neurocognitive problems, with significant interindividual variability in outcome. This study examined genetic polymorphisms associated with variability in neurocognitive outcome.
  
  
  METHODS
  Neurocognitive outcomes were evaluated at the end of therapy in 243 survivors treated on an institutional protocol featuring risk-adapted chemotherapy without prophylactic cranial irradiation. Polymorphisms in genes related to pharmacokinetics or pharmacodynamics of antileukemic agents, drug metabolism, oxidative stress, and attention problems in noncancer populations were examined as predictors of outcome, using multiple general linear models and controlling for age at diagnosis, sex, race, and treatment intensity.
  
  
  RESULTS
  Compared with national norms, the cohort demonstrated significantly higher rates of problems on direct assessment of sustained attention (P = .01) and on parent ratings of attention problems (P = .02). Children with the A2756G polymorphism in methionine synthase (MS) were more likely to demonstrate deficits in attentiveness (P = .03) and response speed (P = .02), whereas those with various polymorphisms in glutathione S-transferase demonstrated increased performance variability (P = .01) and reduced attentiveness (P = .003). Polymorphisms in monoamine oxidase (T1460CA) were associated with increased attention variability (P = .03). Parent-reported attention problems were more common in children with the Cys112Arg polymorphism in apoliopoprotein E4 (P = .01).
  
  
  CONCLUSIONS
  These results are consistent with our previous report of association between attention problems and MS in an independent cohort of long-term survivors of childhood ALL treated with chemotherapy only. The results also raise the possibility of an impact from genetic predispositions related to oxidative stress and CNS integrity.
authors: Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, 262 Danny Thomas Place, MS 735, Memphis, TN 38105-3678, USA. kevin.krull@stjude.org
authors: Kevin R
authors: KR
authors: Krull
authors: Deepa
authors: D
authors: Bhojwani
authors: Heather M
authors: HM
authors: Conklin
authors: Deqing
authors: D
authors: Pei
authors: Cheng
authors: C
authors: Cheng
authors: Wilburn E
authors: WE
authors: Reddick
authors: John T
authors: JT
authors: Sandlund
authors: Ching-Hon
authors: CH
authors: Pui
mesh_terms: D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002648:Child; D003072:Cognition Disorders / Q000150:complications* / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000150:complications* / Q000188:drug therapy / Q000235:genetics*; D017741:Survivors; D016896:Treatment Outcome
references: Neurochem Res. 2007 Apr-May;32(4-5):905-15
references: 17342413
references: AIDS. 2010 Jun 19;24(10):1471-9
references: 20442634
references: Blood. 2002 Jul 1;100(1):67-71
references: 12070010
references: J Int Neuropsychol Soc. 2009 Jan;15(1):31-41
references: 19128526
references: Lipids Health Dis. 2010 Nov 08;9:128
references: 21059196
references: Neurol Sci. 2004 Apr;25(1):13-7
references: 15060810
references: J Clin Oncol. 2009 Dec 10;27(35):5986-92
references: 19884541
references: Neurology. 2011 May 17;76(20):1720-5
references: 21576687
references: Neuroimage. 2011 Jan 15;54(2):1565-77
references: 20804847
references: J Abnorm Child Psychol. 2007 Jun;35(3):393-404
references: 17295064
references: J Neurosci. 2007 Dec 19;27(51):14190-8
references: 18094258
references: J Neuropsychiatry Clin Neurosci. 2005 Fall;17(4):465-71
references: 16387984
references: J Clin Oncol. 2008 Sep 1;26(25):4138-43
references: 18757327
references: Cancer. 2009 Sep 15;115(18):4238-45
references: 19536898
references: J Comp Neurol. 1990 Nov 8;301(2):191-213
references: 2124589
references: Mutat Res. 2001 Oct 1;482(1-2):21-6
references: 11535245
references: J Neurosci. 1998 Sep 1;18(17):6914-27
references: 9712661
references: Magn Reson Imaging. 2008 May;26(4):504-12
references: 18068933
references: Psychooncology. 2003 Sep;12(6):612-9
references: 12923801
references: Curr Opin Psychiatry. 2011 Jan;24(1):49-54
references: 20829693
references: Front Integr Neurosci. 2010 Mar 29;4:8
references: 20556242
references: Hum Mol Genet. 2005 Oct 15;14 Spec No. 2:R275-82
references: 16244326
references: Pediatr Blood Cancer. 2012 Aug;59(2):278-84
references: 21938763
references: Eur J Haematol. 2011 Jun;86(6):477-83
references: 21418106
references: J Natl Cancer Inst. 2012 Sep 19;104(18):1386-95
references: 22927505
references: Clin Endocrinol (Oxf). 2004 Nov;61(5):573-81
references: 15521959
references: Brain Inj. 2011;25(6):596-603
references: 21534737
references: J Stroke Cerebrovasc Dis. 2009 Sep-Oct;18(5):407-8
references: 19717029
references: J Pediatr. 2008 Jan;152(1):101-5
references: 18154909
references: Am J Hum Genet. 2002 Jul;71(1):143-53
references: 12068375
references: Atherosclerosis. 2006 Dec;189(2):264-72
references: 16458317
references: Jpn J Pharmacol. 1991 Jan;55(1):121-8
references: 1904113
references: Neurology. 2007 Jul 17;69(3):243-9
references: 17636061
references: N Engl J Med. 2009 Jun 25;360(26):2730-41
references: 19553647
references: Pediatr Blood Cancer. 2011 Sep;57(3):454-60
references: 21618410
references: Nat Med. 2001 Mar;7(3):285-7
references: 11231620
references: Stat Med. 1990 Jul;9(7):811-8
references: 2218183
references: Neurology. 2008 Jan 1;70(1):9-16
references: 17978275
references: J Natl Cancer Inst. 2010 Jun 16;102(12):881-93
references: 20458059
references: Crit Rev Biochem Mol Biol. 1995;30(6):445-600
references: 8770536