Glutathione S-transferase M1 and T1 polymorphisms may predict adverse effects after therapy in children with medulloblastoma

Abstract

Glutathione S-transferases (GSTs) are polymorphic enzymes that catalyze the glutathione conjugation of alkylating agents, platinum compounds, and free radicals formed by radiation used to treat medulloblastoma. We hypothesized that GST polymorphisms may be responsible, in part, for individual differences in toxicity and responses in pediatric medulloblastoma. We investigated the relationship between GSTM1 and GSTT1 polymorphisms and survival and toxicity in 42 children with medulloblastoma diagnosed and treated at the Texas Children's Cancer Center. We conducted Kaplan-Meier analyses to determine if the GST polymorphisms were related to progression-free survival (PFS) and performed logistic regression to explore associations between GST polymorphisms and occurrence of grade 3 or greater (> or =Gr 3) myelosuppression, ototoxicity, nephrotoxicity, neurotoxicity, and intellectual impairment. Patients with at least one null genotype had a 4.3 (95% confidence interval, 1.1-16.8), 3.7 (1-13.6), and 6.4 (1.2-34) times increased risk for any > or =Gr 3 toxicity, any > or =Gr 3 toxicity excluding peripheral neuropathy, and any > or =Gr 3 toxicity requiring omission or cessation of chemotherapy, respectively. Compared with all others, patients with at least one null genotype had, on average, 27.2 (p x= 0.0002), 29 (p = 0.0004), and 21.7 (p = 0.002) lower full-scale, performance, and verbal intelligence quotient (IQ) scores, respectively. GSTM1 and GSTT1 polymorphisms may predict adverse events, including cognitive impairment after therapy, in patients with medulloblastoma. A larger study to validate these findings is under way.

Fig. 1

Representative PCR products from coamplification of glutathione S-transferase T1 polymorphism (GSTT1; 480 bp), dihydrofolate reductase gene (DHFR; 280 bp), and glutathione S-transferase M1 polymorphism (GSTM1; 215 bp) viewed with an ethidium bromide–stained 2% agarose gel. Abbreviations: T−/+, absence or presence of GSTM1; M−/+, absence or presence of GSTT1.

Fig. 2

Comparisons for serial full-scale intelligence quotient (IQ) measurements by GSTM1T1 combination genotype. (A) Mean slope comparison. (B) All observations. The first assessment was conducted before radiation therapy.