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Basic and Translational Investigations |
Department of Pediatrics (N.B., X.-N.L., L.K., M.C., C.L., M.F.O.) and Childhood Cancer Prevention and Epidemiology Center (N.B., Y.C., C.L., M.F.O.), Texas Children's Cancer Center, Baylor College of Medicine; Learning Support Center, Texas Children's Hospital (S.C.); Department of Epidemiology, Division of Cancer Prevention, University of Texas M. D. Anderson Cancer Center (Y.C.); Division of Biostatistics, Dan L. Duncan Cancer Center, Baylor College of Medicine (T.W.); Department of Audiology, Texas Children's Hospital (L.H.); Houston, TX, USA
Address correspondence to M. Fatih Okcu, 6621 Fannin St., CC1510.00, Houston, TX 77030, USA (mfokcu{at}txccc.org).
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 (
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 Gr 3 toxicity, any Gr 3 toxicity excluding peripheral neuropathy, and any 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.
Key Words: glutathione S-transferase polymorphisms • intellectual impairment • medulloblastoma • pharmacogenetics • toxicity
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