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

¹ Texas Children's Cancer Center, Department of Pediatrics; Childhood Cancer Prevention and Epidemiology Center, Texas Children's Cancer Center; Baylor College of Medicine, Houston, TX
² Learning Support Center, Texas Children's Hospital, Houston, TX
³ Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX
⁴ Division of Biostatistics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX
⁵ Childhood Cancer Prevention and Epidemiology Center, Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX; Department of Epidemiology, Division of Cancer Prevention, The University of Texas M. D. Anderson Cancer Center, Houston, TX
⁶ Department of Audiology, Texas Children's Hospital, Houston, TX

^* To whom correspondence should be addressed. E-mail: mfokcu{at}txccc.org.

	Abstract

Background. 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 response in pediatric medulloblastoma.

Methods. We investigated the relationship between GSTM1 and GSTT1 polymorphisms and survival and toxicity in 42 children with medulloblastoma diagnosed and treated at 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 myelosuppression, ototoxicity, nephrotoxicity, neurotoxicity, and intellectual impairment.

Results. Patients with at least one null genotype had a 4.3 (1.1-16.8), 3.7 (1-13.6), and 6.4 (1.2-34) times increased risk for any Gr 3 toxicity, any Gr 3 toxicity excluding peripheral neuropathy, and any Gr 3 toxicity requiring omission or cessation of chemotherapy, respectively. Compared to all others, patients with at least one null genotype had in average 27.2 (p=0.0002), 29 (p=0.0004), and 21.7 (p=0.002) lower full-scale, performance, and verbal IQ scores, respectively.

Conclusion. GSTM1 and T1 polymorphisms may predict adverse events including cognitive impairment after therapy in patients with medulloblastoma. A larger study to validate these findings is under way

Key Words: pharmacogenetics, glutathione S-transferase polymorphisms, medulloblastoma, intellectual impairment, toxicity

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