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

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  • Author(s): Rednam S;Rednam S; Scheurer ME; Adesina A; Lau CC; Okcu MF
  • Source:
    Pediatric blood & cancer [Pediatr Blood Cancer] 2013 Apr; Vol. 60 (4), pp. 593-8. Date of Electronic Publication: 2012 Oct 12.
  • Publication Type:
    Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: John Wiley Country of Publication: United States NLM ID: 101186624 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1545-5017 (Electronic) Linking ISSN: 15455009 NLM ISO Abbreviation: Pediatr Blood Cancer Subsets: MEDLINE
    • Publication Information:
      Original Publication: Hoboken, N.J. : John Wiley, c 2004-
    • Subject Terms:
      Polymorphism, Single Nucleotide*; Cerebellar Neoplasms/*radiotherapy ; Genetic Predisposition to Disease/*genetics ; Glutathione S-Transferase pi/*genetics ; Hearing Loss/*etiology ; Medulloblastoma/*radiotherapy ; Radiotherapy/*adverse effects; Adolescent ; Cerebellar Neoplasms/genetics ; Cerebellar Neoplasms/mortality ; Child ; Child, Preschool ; Disease-Free Survival ; Female ; Genotype ; Humans ; Immunohistochemistry ; Infant ; Kaplan-Meier Estimate ; Male ; Medulloblastoma/genetics ; Medulloblastoma/mortality ; Neuroectodermal Tumors, Primitive/genetics ; Neuroectodermal Tumors, Primitive/mortality ; Neuroectodermal Tumors, Primitive/radiotherapy
    • Abstract:
      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.
      Procedure: 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.
      (Copyright © 2012 Wiley Periodicals, Inc.)
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    • Grant Information:
      P50 CA127001 United States CA NCI NIH HHS; P50CA127001-04 United States CA NCI NIH HHS
    • Accession Number:
      EC 2.5.1.18 (GSTP1 protein, human)
      EC 2.5.1.18 (Glutathione S-Transferase pi)
    • Publication Date:
      Date Created: 20121016 Date Completed: 20130417 Latest Revision: 20240412
    • Publication Date:
      20240412
    • Accession Number:
      PMC3549321
    • Accession Number:
      10.1002/pbc.24366
    • Accession Number:
      23065688