Glutathione S-transferase P1 single nucleotide polymorphism predicts permanent ototoxicity in children with medulloblastoma.

Abstract

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. 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. 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. 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.