Originally published as JCO Early Release 10.1200/JCO.2006.08.9599 on January 16 2007

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Cisplatin-Induced Long-Term Hearing Impairment Is Associated With Specific Glutathione S-Transferase Genotypes in Testicular Cancer Survivors

Jan Oldenburg, Sigrid M. Kraggerud, Milada Cvancarova, Ragnhild A. Lothe, Sophie D. Fossa

From the Department of Clinical Cancer Research; Department of Cancer Prevention, Institute for Cancer Research; Department of Biostatistics, Rikshospitalet-Radiumhospitalet Medical Center; and the Faculty of Medicine and Department of Molecular Biosciences, University of Oslo, Oslo, Norway

Address reprint requests to Jan Oldenburg, MD, Department of Clinical Cancer Research, Rikshospitalet-Radiumhospitalet Medical Center, Montebello, 0310 Oslo, Norway; e-mail: janolde{at}ulrik.uio.no

PURPOSE: Cisplatin, a cornerstone of combination chemotherapy in the treatment of testicular cancer, induces hearing impairment with considerable interindividual variations. These differences might be a result of functional polymorphisms in cisplatin-detoxifying enzymes like glutathione S-transferases (GSTs).

PATIENTS AND METHODS: We identified 173 cisplatin-treated testicular cancer survivors (TCSs) who had participated in a long-term survey that included audiometric testing and lymphocyte sampling. The hearing decibel thresholds at 4,000 Hz were categorized into leveled scales by normative decibel percentiles. Known functional polymorphisms (positive or negative) in GSTT1 and GSTM1 and codon 105 A/G (Ile/Val) in GSTP1 were analyzed by multiplex polymerase chain reaction, followed by restriction enzyme cutting, and separated by gel electrophoresis.

RESULTS: The risk of having an inferior audiometric result was more than four times higher in TCSs with ¹⁰⁵Ile/¹⁰⁵Ile-GSTP1 or ¹⁰⁵Val/¹⁰⁵Ile-GSTP1 compared with ¹⁰⁵Val/¹⁰⁵Val-GSTP1 (odds ratio [OR] = 4.21; 95% CI, 1.99 to 8.88; P < .001 when modeled by ordinal logistic regression [OLR]). GSTM1 positivity was detrimental for hearing ability. Two combined genotypes were associated with hearing ability. The presence of pattern 1 (GSTT1 positive, GSTM1 positive, and ¹⁰⁵Ile/¹⁰⁵Ile-GSTP1) was associated with hearing impairment (OR = 2.76; 95% CI, 1.35 to 5.64; P = .005, OLR). TCSs with pattern 2 (GSTT1 positive, GSTM1 positive, and ¹⁰⁵Val/¹⁰⁵Val-GSTP1) had better hearing ability than TCSs without this pattern (OR = 5.35; 95% CI, 2.25 to 12.76; P < .001, OLR).

CONCLUSION: The presence of both alleles of ¹⁰⁵Val-GSTP1 offered protection against cisplatin-induced hearing impairment. Two genotype patterns with good and poor protection against cisplatin-induced ototoxicity were identified.

published online ahead of print at www.jco.org on January 16, 2007.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.