Artikel
Confirmation of genetic risk markers of platinum-induced ototoxicity
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Autoren
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Amelie Tillmanns
- Department of Phoniatrics and Pediatric Audiology, University Hospital of Münster, Münster, Germany
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Ross Parfitt
- Department of Phoniatrics and Pediatric Audiology, University Hospital of Münster, Münster, Germany
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Peter Matulat
- Department of Phoniatrics and Pediatric Audiology, University Hospital of Münster, Münster, Germany
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Emaad Abdel-Kahaar
- Institute of Pharmacology of Natural Products and Clinical Pharmacology, University of Ulm, Ulm, Germany
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Lara Maier
- Institute of Pharmacology of Natural Products and Clinical Pharmacology, University of Ulm, Ulm, Germany
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Oliver Zolk
- Institute of Pharmacology of Natural Products and Clinical Pharmacology, University of Ulm, Ulm, Germany
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Susanne Elsner
- Department of Pediatric Oncology and Hematology, University Hospital for Children and Adolescents, Lübeck, Germany
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Eva-Maria Wolschon
- Department of Pediatric Oncology and Hematology, University Hospital for Children and Adolescents, Lübeck, Germany
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Claudia E. Kuehni
- Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland
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Rahel Kuonen
- Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland
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Annette Weiss
- Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland
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Marie-Luisa Garré
- Istituto Giannina Gaslini, Genova, Italy
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Tomas Kepak
- Department of Pediatric Oncology, University Hospital Brno, Brno, Czech Republic
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Katerina Kepakova
- Department of Pediatric Oncology, University Hospital Brno, Brno, Czech Republic
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Jarmila Kruseova
- Department of Children Hemato-Oncology, Motol Teaching Hospital, Prague, Czech Republic
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Ales Luks
- Department of Children Hemato-Oncology, Motol Teaching Hospital, Prague, Czech Republic
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Jeanette Falck Winther
- Danish Cancer Society Research Center, Copenhagen, Denmark
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Line Kenborg
- Danish Cancer Society Research Center, Copenhagen, Denmark
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Herwig Lackner
- Department of Paediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
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Stefan Bielack
- Department of Paediatrics & Oncology, Hematology and Immunology, Centre for Paediatric, Adolescent and Women’s Medicine, Klinikum Stuttgart Olgahospital, Stuttgart, Germany
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Marry van den Heuvel-Eibrink
- Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
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Gabriele Calaminus
- Department of Paediatric Haematology and Oncology, University Hospital Bonn, Bonn, Germany
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Katja Baust
- Department of Paediatric Haematology and Oncology, University Hospital Bonn, Bonn, Germany
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Jörn Beck
- Hospital for Children and Adolescents, University of Erlangen-Nürnberg, Erlangen, Germany
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Leontien Kremer
- Department Pediatric Oncology, Emma Children’s Hospital/Academic Medical Center, Amsterdam, Netherlands
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Eva Clemens
- Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands; Department of Pediatric Hematology and Oncology, Erasmus MC – Sophia Children’s Hospital, Rotterdam, Netherlands
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Thorsten Langer
- Department of Pediatric Oncology and Hematology, University Hospital for Children and Adolescents, Lübeck, Germany
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Antoinette am Zehnhoff-Dinnesen
- Department of Phoniatrics and Pediatric Audiology, University Hospital of Münster, Münster, Germany
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PanCareLIFE consortium
| Veröffentlicht: | 13. September 2019 |
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Gliederung
Abstract
Background: Platinum compounds such as cisplatin or carboplatin are potent antineoplastic agents widely used for a variety of cancer types. Unfortunately, their use leads to dose-limiting side effects such as ototoxicity. Our study aimed at investigating the predictive value of 11 candidate genetic markers in a large non-selected pediatric population of cancer survivors who had been treated with cisplatin and/or carboplatin.
Materials and Methods: As a part of the PanCareLIFE study, the ototoxicity study included 2,696 survivors from 7 European countries treated with cisplatin and/or carboplatin for childhood cancer, resulting in the largest clinical European cohort assembled for this late-effect study. Hearing loss was audiologically classified using the Münster Classification. Three groups were defined, i.e., no hearing loss, minor hearing loss, and clinically relevant hearing loss. Patients were genotyped for single nucleotide polymorphisms (SNPs) in 7 candidate genes. Genetic association analyses were performed considering non-genetic covariates.
Results: 900 patients were included in the final genetic analysis. Multinomial logistic regression was performed to model the relationship between the predictors and membership in the hearing loss group. The model explained 25% of the variance in hearing loss and correctly classified 58% of cases. Significant unique contributions were made by SLC22A2 rs316019 (P=0.017), age at the start of platinum treatment (P=1.46x10–17), cranial radiation (P=5.42x10–6), and the cumulative dose of cisplatin (P=5.86x10–19). Addition of the rs316019 genetic marker to the non-genetic risk factors (age, dose, cranial radiation) improved the area under the ROC curve only marginally (0.731 vs. 0.730).
Discussion: Our study confirmed one potential genetic marker, rs316019 in SLC22A2. Its predictive value, however, is low.
Conclusion: Due to the heterogeneity of results from genetic association studies performed so far, the evidence seems not yet sufficient to recommend screening for specific markers. Advances in the understanding of the pathophysiologic mechanisms of cisplatin-induced ototoxicity, as well as future genome-wide association studies, may help identify suitable genetic markers.
Acknowledgement: This work was supported by the PanCareLIFE project that has received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement no. 602030.
Text
Background
Platinum compounds such as cisplatin or carboplatin are potent antineoplastic agents widely used for a variety of cancer types. Unfortunately, their use leads to dose-limiting side effects such as ototoxicity. Our study aimed at investigating the predictive value of 11 candidate genetic markers in a large non-selected pediatric population of cancer survivors who had been treated with cisplatin and/or carboplatin.
Material and Methods
As a part of the PanCareLIFE study, the ototoxicity study included 2,696 survivors from 7 European countries treated with cisplatin and/or carboplatin for childhood cancer, resulting in the largest clinical European cohort assembled for this late-effect study. Hearing loss was audiologically classified using the Münster Classification. Three groups were defined, i.e., no hearing loss, minor hearing loss, and clinically relevant hearing loss. Patients were genotyped for single nucleotide polymorphisms (SNPs) in 11 candidate genes. Genetic association analyses were performed considering non-genetic covariates.
Results
900 patients were included In the final genetic analysis (Figure 1 [Fig. 1]). Multinomial logistic regression was performed to model the relationship between the predictors and membership in the hearing loss group. The model explained 25% of the variance in hearing loss and correctly classified 58% of cases. Significant unique contributions were made by SLC22A2 rs316019 (P=0.017), age at the start of platinum treatment (P=1.46x10-17), cranial radiation (P=5.42x10-6), and the cumulative dose of cisplatin (P=5.86x10-19) (Table 1 [Tab. 1]). Addition of the rs316019 genetic marker to the non-genetic risk factors (age, dose, cranial radiation) improved the area under the ROC curve only marginally (0.731 vs. 0.730).
Discussion
Our study confirmed one potential genetic marker, rs316019 in SLC22A2. Its predictive value, however, is low.
Conclusion
Due to the heterogeneity of results from genetic association studies performed so far, the evidence seems not yet sufficient to recommend screening for specific markers. Advances in the understanding of the pathophysiologic mechanisms of cisplatin-induced ototoxicity, as well as future genome-wide association studies, may help identify suitable genetic markers.
Acknowledgement: This work was supported by the PanCareLIFE project that has received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement no. 602030.
