Cisplatin-induced long-term hearing impairment is associated with specific glutathione s-transferase genotypes in testicular cancer survivors.
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.
Oldenburg
Jan
J
Department of Clinical Cancer Research, Rikshospitalet-Radiumhospitalet Medical Center, Montebello, Oslo, Norway. janolde@ulrik.uio.no
Kraggerud
Sigrid M
SM
Cvancarova
Milada
M
Lothe
Ragnhild A
RA
Fossa
Sophie D
SD
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
C413545:glutathione S-transferase T1; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D002945:Cisplatin