title: Cisplatin-induced long-term hearing impairment is associated with specific glutathione s-transferase genotypes in testicular cancer survivors.
abstract: OBJECTIVE
  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).
  
  
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Clinical Cancer Research, Rikshospitalet-Radiumhospitalet Medical Center, Montebello, Oslo, Norway. janolde@ulrik.uio.no
authors.forename: Jan
authors.initials: J
authors.lastname: Oldenburg
authors.forename: Sigrid M
authors.initials: SM
authors.lastname: Kraggerud
authors.forename: Milada
authors.initials: M
authors.lastname: Cvancarova
authors.forename: Ragnhild A
authors.initials: RA
authors.lastname: Lothe
authors.forename: Sophie D
authors.initials: SD
authors.lastname: Fossa
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001299:Audiometry; D016022:Case-Control Studies; D002945:Cisplatin / Q000009:adverse effects* / Q000627:therapeutic use; D016001:Confidence Intervals; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D051549:Glutathione S-Transferase pi / Q000235:genetics*; D005982:Glutathione Transferase / Q000235:genetics*; D034381:Hearing Loss / Q000139:chemically induced* / Q000175:diagnosis / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D016017:Odds Ratio; D011336:Probability; D012189:Retrospective Studies; D012720:Severity of Illness Index; D017741:Survivors; D013736:Testicular Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D013997:Time Factors
chemical_list: C413545:glutathione S-transferase T1; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D002945:Cisplatin