Glutathione S-transferase P1 single nucleotide polymorphism predicts permanent ototoxicity in children with medulloblastoma.
BACKGROUND
Glutathione S-transferase (GST) enzymes are involved in detoxifying chemotherapy and clearing reactive oxygen species formed by radiation. We explored the relationship between the host GSTP1 105 A > G polymorphism (rs1695), tumor GSTpi protein expression, and clinical outcomes in pediatric medulloblastoma. We hypothesized that the GSTP1 105 G-allele and increased tumor GSTpi expression would be associated with lower progression-free survival and fewer adverse events.


METHODS
The study included 106 medulloblastoma/primitive neuroectodermal tumor (PNET) patients seen at Texas Children's Cancer Center. Genotyping was performed using an Illumina HumanOmni1-Quad BeadChip and GSTpi expression was assessed using immunohistochemistry. We used the Kaplan-Meier method for survival analyses and logistic regression for toxicity comparisons.


RESULTS
Patients with a GSTP1 105 AG/GG genotype (vs. AA) or who had received high dose craniospinal radiation (≥34 Gy vs. <26 Gy) had a greater risk of requiring hearing aids than their counterparts (OR 4.0, 95% CI 1.2-13.6, and OR 3.1, 95% CI 1.1-8.8, respectively, n = 69). Additionally, there was a statistically significant interaction between these variables. Compared with the lowest risk group (GSTP1 105 AA-low dose radiation), patients with a GSTP1 105 AG/GG genotype who received high dose radiation were 8.4 times more likely to require hearing aids (95% CI 1.4-49.9, p-trend = 0.005, n = 69). When adjusted for age, cumulative cisplatin dose, and amifostine use, the association remained.


CONCLUSIONS
The GSTP1 105 G-allele is associated with permanent ototoxicity in pediatric medulloblastoma/PNET and strongly interacts with radiation dose. Patients with this allele should be considered for clinical trials employing radiation dose modifications and cytoprotectant strategies.
Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA. sprednam@txch.org
Surya
S
Rednam
Michael E
ME
Scheurer
Adekunle
A
Adesina
Ching C
CC
Lau
Mehmet Fatih
MF
Okcu
D000293:Adolescent; D002528:Cerebellar Neoplasms / Q000235:genetics / Q000401:mortality / Q000532:radiotherapy*; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D051549:Glutathione S-Transferase pi / Q000235:genetics*; D034381:Hearing Loss / Q000209:etiology*; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D053208:Kaplan-Meier Estimate; D008297:Male; D008527:Medulloblastoma / Q000235:genetics / Q000401:mortality / Q000532:radiotherapy*; D018242:Neuroectodermal Tumors, Primitive / Q000235:genetics / Q000401:mortality / Q000532:radiotherapy; D020641:Polymorphism, Single Nucleotide; D011878:Radiotherapy / Q000009:adverse effects*
C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi