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

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
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.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Cisplatin-induced long-term somatic sequelae in testicular cancer survivors (TCSs) include ototoxicity.^1,2 Hearing impairment at high frequencies (4,000 to 8,000 Hz) was found to persist in 20% of TCSs.³ Loss of outer hair cells of the organ of Corti, probably as a result of oxidative stress, has been demonstrated as a pathogenic mechanism for cisplatin-induced ototoxicity.⁴

Ototoxicity in patients receiving similar cumulative cisplatin doses and application schedules demonstrates considerable interindividual variations. These variations were too great to be explained by the respective pharmacokinetics in an animal model.⁵ This led to the hypothesis that some TCSs are carriers of polymorphisms in genes encoding drug-metabolizing enzymes that render them especially susceptible to such late effects.⁵ Data from animal models suggest that glutathione S-transferases (GSTs) possibly protect against ototoxicity. GSTs are expressed in the mammalian cochlea,⁶ where their activity as well as the level of glutathione decrease when cisplatin-induced ototoxicity develops.⁷ Furthermore, the sensitive period for drug-induced ototoxicity in fetal rats ends when GSTs start to be expressed.⁸

The genes encoding the enzymes GSTM1, GSTT1, and GSTP1 are polymorphic in humans.^9-11 Deletion polymorphisms in GSTM1 and GSTT1 leading to lack of GSTM1 and GSTT1 are reported to occur in 50%¹⁰ and 20% of the white population, respectively.¹² The single nucleotide polymorphism (SNP) at base pair (bp) 313 in GSTP1, between adenosine (A) and guanine (G), leads to the expression of either isoleucine (Ile) or valine (Val) at codon 105 and thereby to an altered catalytic enzyme activity. Functional GST polymorphisms are associated with the incidence of several tumors^13-16 and affect both the treatment response^17-20 and the chemotherapy-related adverse effects.^21,22 In 39 patients, Peters et al²³ demonstrated a significant association between cisplatin-induced hearing impairment and the expression of GSTM3, but not GSTM1, GSTT1, or GSTP1. To the best of the authors' knowledge, no larger cohorts have been examined for the association between cisplatin-induced ototoxicity and GST polymorphisms. Whether or not GSTT1 and GSTM1 polymorphisms are associated with a susceptibility of hearing impairment by noise or aging via reducing oxidative stress has not been settled.^24,25 In the present study, we aimed to investigate the association between cisplatin-induced hearing impairment and GSTT1, GSTP1, and GSTM1 polymorphisms in a large sample of TCSs.

	PATIENTS AND METHODS

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Patients and Samples
From 1998 to 2001, TCSs treated from 1980 to 1994 and aged between 18 and 75 years were invited to take part in a multicenter long-term survey, which consisted of a questionnaire and an outpatient visit.²⁶ Postorchiectomy treatment was principally applied according to specified protocols defined by the Swedish-Norwegian Testicular Cancer Project, or by the European Organisation for Research and Treatment of Cancer Genito-Urinary Group, and by the Medical Research Council Testicular Cancer Working Party as described previously.²⁷ Most patients treated with chemotherapy had received cisplatin in combination with bleomycin, etoposide, or vinblastine as three to four courses of bleomycin, etoposide, and cisplatin or cisplatin, vinblastine, and bleomycin. These regimens were applied in conjunction with a rigorous and standardized hydration regimen in all patients. The present study includes only TCSs who had been treated with cisplatin-based chemotherapy at the Norwegian Radium Hospital and in whom an audiometry was performed during the survey's outpatient consultation.

Genotyping
Whole-blood EDTA samples were collected, lymphocyte DNA extracted, and submitted to genetic analyses. In GSTT1 and GSTM1, known inherited homozygous deletions are equivalent to nonfunctional enzymes. A functional SNP between A and G at bp 315 in the GSTP1 gene leads to the expression of either Ile or Val at codon 105. GST analysis was performed according to a previously described multiplex polymerase chain reaction (PCR) protocol²⁸; 50 to 100 ng of DNA; 30 pmol of each of the primers for GSTM1, GSTT1, and GSTP1; 10 pmol of the GSTM2 antisense primer; 1.4 mmol/L of MgCl₂; PCR buffer II from Perkin Elmer (Wellesley, MA; MgCl₂ free); and 0.75 U of Taq polymerase were mixed. The fragment lengths of the PCR products were 480 bp for GSTT1, 294 bp for GSTP1, 275 bp for GSTM1, and 175 bp for GSTM2.

The PCR product (20 µL, unpurified) was subjected to restriction enzyme fragment analysis with 8 units of Alw261 (MBI Fermentas, Hanover, MD). The bands for GSTT1 and GSTM2 remain uncut. GSTP1 fragments contain 234 and 60 bp in case of a G in the sequence at codon 105 in exon 5. GSTM1 contains a nonpolymorphic Alw1261 restriction site and is digested to 195- and 80-bp fragments in all samples (ie, those positive for GSTM1 alleles). Finally, the products were analyzed by gel electrophoresis in a 4% agarose gel (NuSieve 3:1; FCM Bioproducts, Rockland, ME).

Audiometry
Air and bone conduction thresholds at nine frequencies within the range of 250 to 8,000 Hz were measured using a Micromate 304 Screening Audiometer (Madsen Electronics, Taastrup, Denmark). The present analysis was based on the 4,000-Hz decibel threshold. This frequency represents the upper limit of the language communication range and is vulnerable to cisplatin toxicity. Engdahl et al²⁹ provided the decibel thresholds for several frequencies of 51,975 Norwegian participants separately for sex and decadal age groups. We used the 10th, 25th, 50th, 75th, and 90th percentiles at 4,000 Hz, which were provided for 23,446 males in Table 4 of Engdahl et al.²⁹

Individual audiogram scores (both ears averaged) were ranked using a three-level scale, illustrated in Figure 1, defined by the following three percentiles of the normal population: 50th percentile, no hearing impairment; 50th to 74th percentile, moderate hearing impairment; and 75th percentile, severe hearing impairment. Furthermore, a six-level categorization, as defined by the five percentiles, was applied for the ordinal logistic regression (OLR) analyses described in the next section.

View larger version (18K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Categorization of hearing impairment based on audiogram percentiles of the Norwegian general population, exemplified for 50- to 59-year-old men, according to Table 4 of Engdahl et al.29

In addition, the association was studied using logistic regression modeling. Two OLRs were performed to investigate the risk of hearing impairment measured on two- and six-level scales. The model with six categories demonstrated the best fit. Unfortunately, our sample size was too small to fit such a model with more than one covariate (one distinct genotype). Thus, we had to use a simplified model with hearing impairment as a binary outcome for adjustment for several covariates.

The strength of a possible association was expressed by odds ratio (OR) with its respective 95% CI and P value. Because of multiple testing, P < .01 was considered statistically significant; all tests were two tailed.

Ethics
The Committee for Medical Ethics of Health Region II of Norway approved the protocol of the study. All patients provided written informed consent for study participation.

	RESULTS

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A total of 173 TCSs were eligible for the present study and had the following characteristics: median age at survey, 42 years (range, 24 to 73 years); cumulative cisplatin dose, 402 mg/m² (range, 193 to 1,571 mg/m²); and interval between start of chemotherapy and the audiometric examination, 11.8 years (range, 4 to 20 years). A binary logistic regression, which included all three single polymorphisms, age, and cumulative cisplatin dose, revealed that only the latter was significantly associated with hearing impairment. The association between hearing ability and GSTP1 genotypes was at the border of significance (P = .036 and P = .047 are above the level of significance of .01, which is adjusted for multiple testing). Compared with TCSs with¹⁰⁵Val/¹⁰⁵Val-GSTP1, TCSs with the ¹⁰⁵Ile/¹⁰⁵Ile-GSTP1 and ¹⁰⁵Val/¹⁰⁵Ile-GSTP1 genotypes were at a 3.26 to 3.45 higher risk of hearing results below the 75th percentile of age-matched controls. This ratio increased by adjustment for the cumulative cisplatin dose and GSTM1. GSTM1, despite a nonsignificant crude association, was at the border of significance in the adjusted model. This suggested an interaction between the variables that we will describe in more detail.

Single Genotypes
Presence of GSTT1 and GSTM1 was found in 84% and 54% of the TCSs, respectively (Table 1). Forty-one percent and 43% of TCSs had the ¹⁰⁵Ile/¹⁰⁵Ile-GSTP1 and ¹⁰⁵Val/¹⁰⁵Ile-GSTP1 genotype, respectively. The remaining 16% of TCSs (28 TCSs) were homozygous for ¹⁰⁵Val/¹⁰⁵Val-GSTP1. The cumulative cisplatin dose did not differ significantly between the TCS cohorts of single genotypes, except for GSTM1 (TCSs negative for GSTM1 received, on average, an additional 52 mg/m² of cisplatin; Table 1).

View larger version (24K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Association between glutathione S-transferase (GST) genotypes and cisplatin-induced hearing impairment (P values indicate the significance of difference between the groups). (A) GSTP1 polymorphisms; (B) presence of GSTM1 among 120 testicular cancer survivors with GSTT1 positivity and either 105Ile/105Ile-GSTP1 or 105Val/105Ile-GSTP1; (C) patterns 1 and 2.

Genotype Combinations
Five of the 12 possible GST genotype combination patterns comprised 20 or more TCSs, and only those patterns were submitted to further statistical analysis (Table 3). The cumulative cisplatin doses were not significantly different between these five cohorts. Two of the five combined genotypes showed significant associations with the audiometric results; 21 (70%) of 30 TCSs with GSTT1 positivity, GSTM1 positivity, and ¹⁰⁵Ile/¹⁰⁵Ile-GSTP1 (pattern 1) had hearing impairment compared with 68 (48%) of 143 TCSs without this pattern (² trend, P = .004; Table 3). The strength of the statistical association was even more apparent when the six-level scale was applied. The odds for reduced hearing in TCSs with pattern 1 compared with TCSs without this genotype pattern were almost three times higher (OR = 2.76; 95% CI, 1.35 to 5.64; P = .005, OLR; Fig 2C).

	DISCUSSION

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In this large sample of TCSs, long-term hearing impairment was significantly associated with the cumulative cisplatin dose and with certain GST genotypes. The homozygous ¹⁰⁵Val/¹⁰⁵Val-GSTP1 genotype exhibited protection against the cisplatin-induced hearing impairment when compared with the ¹⁰⁵Ile/¹⁰⁵Ile-GSTP1 or ¹⁰⁵Ile/¹⁰⁵Val-GSTP1 genotypes. ¹⁰⁵Val-GSTP1 demonstrates features of a recessive allele, which means that both copies are required to be present to prevent cisplatin-induced ototoxicity. For the heterozygous ¹⁰⁵Ile/¹⁰⁵Val-GSTP1, a linear relationship would imply a phenotype midway between those two homozygous ones. This was not the case because the degree of hearing impairment of TCSs with the heterozygous ¹⁰⁵Val/¹⁰⁵Ile-GSTP1 genotype is similar to that of TCSs with a homozygous ¹⁰⁵Ile/¹⁰⁵Ile-GSTP1 genotype.

TCSs with the genotype pattern of GSTT1 positivity, GSTM1 positivity, and ¹⁰⁵Val/¹⁰⁵Val-GSTP1 (pattern 2) had a highly significant better hearing ability than TCSs without this pattern. This result mainly reflects the protective effect of the ¹⁰⁵Val/¹⁰⁵Val-GSTP1 genotype because most TCSs with that single genotype belonged to the pattern 2 group. TCSs with pattern 1 (GSTT1 positivity, GSTM1 positivity, and ¹⁰⁵Ile/¹⁰⁵Ile-GSTP1) had a significantly inferior hearing ability than TCSs without pattern 1. Again, GSTP1 seems to exert a predominant effect because the results are comparable to the results from the group of 71 TCSs with the single genotype of ¹⁰⁵Ile/¹⁰⁵Ile-GSTP1. However, one would possibly expect the functional GSTT1 and GSTM1 to compensate for the assumed lower cisplatin detoxification efficacy of the enzyme ¹⁰⁵Ile/¹⁰⁵Ile-GSTP1, but instead, the opposite seems to be the case. In addition, an adjusted OR of 2.36 for TCSs with GSTM1 positivity compared with TCSs with GSTM1 negativity indicated a detrimental effect of functional GSTM1. To further evaluate this finding, we performed a subanalysis restricted to the 120 TCSs with functional GSTT1 and either ¹⁰⁵Ile/¹⁰⁵Ile-GSTP1 or ¹⁰⁵Ile/¹⁰⁵Val-GSTP1; indeed, those TCSs with GSTM1 positivity heard 4,000 Hz tones less well than those with GSTM1 negativity. Speculatively, this might be explained by a competition on glutathione as substrate of both GSTP1 and GSTM1. GSTM1 may use glutathione preferably for other reactions than detoxification of cisplatin and thus might, as a result of a limited amount of available substrate, impair the more efficient GSTP1 enzymes. Unfortunately, the applied genotyping analysis precluded differentiation between homo- and heterozygous functional GSTM1 alleles and, thus, demonstration of an assumed gene-dosage effect as shown for the breast cancer risk.³⁰

In a previous study by Peters et al,²³ polymorphisms in GSTT1, GSTM1, or GSTP1 were not found to be significantly associated with cisplatin-induced hearing impairment, which might be a result of a different methodologic approach and a smaller sample size (39 patients, ages 3 to 22 years during treatment). However, functional GSTP1 polymorphisms have been found to be associated with the efficacy and toxicity of chemotherapy.

Patients with Hodgkin's lymphoma and the genotype ¹⁰⁵Val/¹⁰⁵Val-GSTP1 had a 100% 5-year survival rate compared with rates of 74% and 47% in patients with ¹⁰⁵Val/¹⁰⁵Ile-GSTP1 or ¹⁰⁵Ile/¹⁰⁵Ile-GSTP1 genotypes, respectively.¹⁸ Furthermore, patients with the ¹⁰⁵Val/¹⁰⁵Ile-GSTP1 or ¹⁰⁵Val/¹⁰⁵Val GSTP1 genotypes were more prone to develop a chemotherapy-induced leukemia than patients with the ¹⁰⁵Ile/¹⁰⁵Ile-GSTP1 genotype.³¹ This relationship was especially apparent in patients who had received known GSTP1 substrates such as cyclophosphamide, chlorambucil, or doxorubicin. Both studies conclude that the allele ¹⁰⁵Val-GSTP1 confers a lower detoxification capability and, hence, leads to an increased chemotherapy-induced toxicity. The toxicity directed towards the malignant cells was intended and beneficial for survival of Hodgkin's lymphoma patients, whereas the toxic effect on bone marrow stem cells was unintended and pernicious with respect to the risk of developing a chemotherapy-induced leukemia. Surprisingly, TCSs homozygous for the allele ¹⁰⁵Val-GSTP1 had experienced protection against chemotherapy-induced ototoxicity. Comparable results were found by Lecomte et al³² in a study of oxaliplatin-induced neurotoxicity in patients with gastrointestinal cancer. They found that patients (n = 25, 39%) with the allele GSTP1-G, which codes for ¹⁰⁵Val-GSTP1, were protected against neuropathy compared with patients without this allele (unadjusted OR, 5.75; 95% CI, 1.1 to 30.7; P = .02). The apparent contradiction between these studies is probably a result of a variant substrate specificity of GSTP1.

The examined SNP leads to the substitution of Ile by Val at codon 105. This residue determines the specific activity and affinity for electrophilic substrates, and amino acid variations have been shown to alter the detoxification efficacy for such compounds.³³ The potential protective effect of the ¹⁰⁵Val/¹⁰⁵Val-GSTP1 genotype observed in the present series is in concordance with a previously reported enhanced efficacy of cisplatin detoxification by human ¹⁰⁵Val/¹⁰⁵Val-GSTP1 compared with the more frequent genotype ¹⁰⁵Ile/¹⁰⁵Ile-GSTP1, which in turn more efficiently protected against thiotepa toxicity.³⁴ Furthermore, Ishimoto et al³⁴ reported a four- to five-fold cytoprotection level of ¹⁰⁵Val-GSTP1 compared with ¹⁰⁵Ile-GSTP1. Intriguingly, this ratio corresponds well with the risk of an inferior hearing result related to this polymorphism as observed in the present study.

The study by Lecomte et al³² indicated that protection by GSTP1-G against oxaliplatin-induced neurotoxicity is related to the inactivation of the stress-inducible kinase JNK.³⁵ The authors hypothesized that GSTP1-G could be more efficient in this regard. Because inactivation of JNK limits the ototoxic effects of cisplatin,³⁶ this effect could also prevent oxaliplatin-induced neurotoxicity. These cell signaling alterations might also account, at least in part, for our observations. However, it seems inappropriate to speculate on whether the first, second, or possibly an additional molecular pathway is more important, and further investigations of the pathophysiologic effects of polymorphic GSTs are necessary.

A weakness of the present study is the lack of pretreatment audiometric results, which probably would have increased the precision of our results. However, the size and homogeneity of the present study minimizes the risk of random association and confounding.³⁷ Furthermore, the more refined six-level categorization, compared with binary (yes/no) or three-level categoric scales of hearing impairment, increased the statistical strength of genotype association, supporting the hypothesis of a true association.

The excellent prognosis of low-risk testicular cancer patients allows investigators to focus on treatment-induced toxicity. In the adjuvant setting, patients should carefully be informed about anticipated adverse effects when balancing the pros and cons of further treatment options. When the data are validated in an independent prospective study, GST genotyping might represent a welcomed step towards a more individualized counseling, especially for patients in whom optimal hearing ability is critical (eg, musicians).

In conclusion, our retrospective study revealed a clinically relevant protection against cisplatin-induced hearing impairment by the genotype ¹⁰⁵Val/¹⁰⁵Val-GSTP1. Furthermore, one genotype combination (pattern 2) with a highly protective effect against cisplatin-induced ototoxicity and one combination (pattern 1) associated with increased susceptibility of cisplatin-induced ototoxicity were identified.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
The authors indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Conception and design: Jan Oldenburg, Sophie D. Fossa

Administrative support: Ragnhild A. Lothe, Sophie D. Fossa

Provision of study materials or patients: Sigrid M. Kraggerud, Ragnhild A. Lothe, Sophie D. Fossa

Collection and assembly of data: Jan Oldenburg, Sigrid M. Kraggerud, Sophie D. Fossa

Data analysis and interpretation: Jan Oldenburg, Sigrid M. Kraggerud, Milada Cvancarova, Ragnhild A. Lothe, Sophie D. Fossa

Manuscript writing: Jan Oldenburg, Milada Cvancarova, Sophie D. Fossa

Final approval of manuscript: Jan Oldenburg, Sigrid M. Kraggerud, Milada Cvancarova, Ragnhild A. Lothe, Sophie D. Fossa

	Appendix

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	NOTES

 
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.

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Submitted September 5, 2006; accepted November 29, 2006.

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