Antioxidant enzyme polymorphisms and neuropsychological outcomes in medulloblastoma survivors: a report from the Childhood Cancer Survivor Study.
Psychological or neurocognitive impairment is often seen in medulloblastoma survivors after craniospinal radiation; however, significant variability in outcomes exists. This study investigated the role of antioxidant enzyme polymorphisms in moderating this outcome and hypothesized that patients who had polymorphisms associated with lower antioxidant enzyme function would have a higher occurrence of impairment. From the Childhood Cancer Survivor Study (CCSS) cohort, 109 medulloblastoma survivors and 143 siblings were identified who completed the CCSS Neurocognitive Questionnaire (NCQ) and the Brief Symptom Inventory-18 (BSI-18) and who provided buccal DNA samples. Real-time polymerase chain reaction (PCR) allelic discrimination was used for SOD2 (rs4880), GPX1 (rs1050450), and GSTP1 (rs1695 and rs1138272) genotyping and PCR for GSTM1 and GSTT1 gene deletions. Outcomes on NCQ and BSI-18 subscale scores were examined in association with genotypes and clinical factors, including age at diagnosis, sex, and radiation dose, using univariate and multivariate analysis of variance. Patients <7 years of age at diagnosis displayed more problems with task efficiency (P < .001) and fewer problems with somatic complaints (P = .004) than did patients ≥7 years of age. Female patients reported more organization problems than did male patients (P = .02). Patients with homozygous GSTM1 gene deletion reported higher anxiety (mean null genotype = 47.3 ± 9.2, non-null = 43.9 ± 7.8; P = .04), more depression (null = 51.0 ± 9.8, non-null = 47.0 ± 9.4; P = .03), and more global distress (null = 50.2 ± 9.7, non-null = 45.2 ± 9.9; P = .01). All associations for the GSTM1 polymorphism remained statistically significant in a multivariate model controlling for age, sex, and radiation dose. Homozygous GSTM1 gene deletion was consistently associated with greater psychological distress in medulloblastoma survivors across multiple domains, suggesting that this genotype may predispose patients for increased emotional late effects.
Department of Pediatrics, Texas Children’s Cancer Center, Baylor College of Medicine, Houston, TX, USA. jxbracke@txch.org
Julienne
J
Brackett
Kevin R
KR
Krull
Michael E
ME
Scheurer
Wei
W
Liu
Deo Kumar
DK
Srivastava
Marilyn
M
Stovall
Thomas E
TE
Merchant
Roger J
RJ
Packer
Leslie L
LL
Robison
M Fatih
MF
Okcu
D000293:Adolescent; D000328:Adult; D000975:Antioxidants; D002528:Cerebellar Neoplasms / Q000523:psychology / Q000532:radiotherapy*; D002648:Child; D016371:Cranial Irradiation / Q000009:adverse effects*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D005979:Glutathione Peroxidase / Q000235:genetics; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D008297:Male; D008527:Medulloblastoma / Q000523:psychology / Q000532:radiotherapy*; D001523:Mental Disorders / Q000209:etiology / Q000235:genetics*; D008875:Middle Aged; D060885:Multiplex Polymerase Chain Reaction; D009483:Neuropsychological Tests; D020641:Polymorphism, Single Nucleotide; D060888:Real-Time Polymerase Chain Reaction; D013482:Superoxide Dismutase / Q000235:genetics; D017741:Survivors; D055815:Young Adult; D000094765:Glutathione Peroxidase GPX1; D000099156:Superoxide Dismutase 2
D000975:Antioxidants; D005979:Glutathione Peroxidase; D005982:Glutathione Transferase; D013482:Superoxide Dismutase; D000094765:Glutathione Peroxidase GPX1; D000099156:Superoxide Dismutase 2; C000722067:GPX1 protein, human