Thorsten Langer1, Eva Clemens2, Linda Broer3, Lara Maier4, André G Uitterlinden3, Andrica C H de Vries2, Martine van Grotel5, Saskia F M Pluijm5, Harald Binder6, Benjamin Mayer7, Annika von dem Knesebeck1, Julianne Byrne8, Eline van Dulmen-den Broeder9, Marco Crocco10, Desiree Grabow11, Peter Kaatsch11, Melanie Kaiser11, Claudia Spix11, Line Kenborg12, Jeanette F Winther13, Catherine Rechnitzer14, Henrik Hasle15, Tomas Kepak16, Anne-Lotte F van der Kooi17, Leontien C Kremer18, Jarmila Kruseova19, Stefan Bielack20, Benjamin Sorg20, Stefanie Hecker-Nolting20, Claudia E Kuehni21, Marc Ansari22, Martin Kompis23, Heleen van der Pal18, Ross Parfitt24, Dirk Deuster24, Peter Matulat24, Amelie Tillmanns24, Wim J E Tissing25, Jörn D Beck26, Susanne Elsner27, Antoinette Am Zehnhoff-Dinnesen24, Marry M van den Heuvel-Eibrink2, Oliver Zolk28. 1. Department of Pediatric Oncology and Hematology, University Hospital for Children and Adolescents, Lübeck, Germany. 2. Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Department of Pediatric Oncology, Erasmus MC - Sophia Children's Hospital, Rotterdam, the Netherlands. 3. Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands. 4. Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University Medical Center, Ulm, Germany. 5. Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands. 6. German Childhood Cancer Registry, Institute of Medical Biostatistics, Epidemiology and Informatics, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany; Institute of Medical Biometry and Statistics, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany. 7. Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm, Germany. 8. Boyne Research Institute, Drogheda, Ireland. 9. Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Department of Pediatric Hematology and Oncology, VU Medical Center, Amsterdam, the Netherlands. 10. Department of Neurooncology, Istituto Giannina Gaslini, Genova, Italy. 11. German Childhood Cancer Registry, Institute of Medical Biostatistics, Epidemiology and Informatics, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany. 12. Danish Cancer Society Research Center, Childhood Cancer Research Group, Copenhagen, Denmark. 13. Danish Cancer Society Research Center, Childhood Cancer Research Group, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark. 14. Copenhagen University Hospital Rigshospitalet, Department of Pediatrics and Adolescent Medicine, Copenhagen, Denmark. 15. Aarhus University Hospital, Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark. 16. University Hospital Brno, Brno, Czech Republic; International Clinical Research Center (FNUSA-ICRC), Brno, Czech Republic. 17. Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Department of Obstetrics and Gynecology, Erasmus MC - Sophia Children's Hospital, the Netherlands. 18. Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Department of Pediatric Oncology, Academic Medical Center Amsterdam, Amsterdam, the Netherlands. 19. Department of Children Hemato-Oncology, Motol University Hospital Prague, Prague, Czech Republic. 20. Department of Pediatric Oncology, Hematology, Immunology, Stuttgart Cancer Center, Olgahospital, Stuttgart, Germany. 21. Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland; Paediatric Oncology, Dept. of Paediatrics, Inselspital, University of Bern, Switzerland. 22. Department of Pediatrics, Oncology and Hematology Unit, University Hospital of Geneva, Cansearch Research Laboratory, Geneva University, Switzerland. 23. Department of Otolaryngology, Head and Neck Surgery, Inselspital, University of Berne, Switzerland. 24. Department of Phoniatrics and Pedaudiology, University Hospital Münster, Westphalian Wilhelm University, Münster, Germany. 25. Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Department of Pediatric Oncology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. 26. Hospital for Children and Adolescents, University of Erlangen-Nuremberg, Erlangen, Germany. 27. Institute for Social Medicine and Epidemiology, University of Lübeck, Lübeck, Germany. 28. Institute of Clinical Pharmacology, Immanuel Klinik Rüdersdorf, Brandenburg Medical School Theodor Fontane, Germany; Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University Medical Center, Ulm, Germany. Electronic address: oliver.zolk@mhb-fontane.de.
Abstract
BACKGROUND: Irreversible sensorineural hearing loss is a common side effect of platinum treatment with the potential to significantly impair the neurocognitive, social and educational development of childhood cancer survivors. Genetic association studies suggest a genetic predisposition for cisplatin-induced ototoxicity. Among other candidate genes, thiopurine methyltransferase (TPMT) is considered a critical gene for susceptibility to cisplatin-induced hearing loss in a pharmacogenetic guideline. The aim of this cross-sectional cohort study was to confirm the genetic associations in a large pan-European population and to evaluate the diagnostic accuracy of the genetic markers. METHODS: Eligibility criteria required patients to be aged less than 19 years at the start of chemotherapy, which had to include cisplatin and/or carboplatin. Patients were assigned to three phenotype categories: no, minor and clinically relevant hearing loss. Fourteen variants in eleven candidate genes (ABCC3, OTOS, TPMT, SLC22A2, NFE2L2, SLC16A5, LRP2, GSTP1, SOD2, WFS1 and ACYP2) were investigated. Multinomial logistic regression was performed to model the relationship between genetic predictors and platinum ototoxicity, adjusting for clinical risk factors. Additionally, measures of the diagnostic accuracy of the genetic markers were determined. RESULTS: 900 patients were included in this study. In the multinomial logistic regression, significant unique contributions were found from SLC22A2 rs316019, the age at the start of platinum treatment, cranial radiation and the interaction term [platinum compound]∗[cumulative dose of cisplatin]. The predictive performance of the genetic markers was poor compared with the clinical risk factors. CONCLUSIONS: PanCareLIFE is the largest study of cisplatin-induced ototoxicity to date and confirmed a role for the polyspecific organic cation transporter SLC22A2. However, the predictive value of the current genetic candidate markers for clinical use is negligible, which puts the value of clinical factors for risk assessment of cisplatin-induced ototoxicity back into the foreground.
BACKGROUND: Irreversible sensorineural hearing loss is a common side effect of platinum treatment with the potential to significantly impair the neurocognitive, social and educational development of childhood cancer survivors. Genetic association studies suggest a genetic predisposition for cisplatin-induced ototoxicity. Among other candidate genes, thiopurine methyltransferase (TPMT) is considered a critical gene for susceptibility to cisplatin-induced hearing loss in a pharmacogenetic guideline. The aim of this cross-sectional cohort study was to confirm the genetic associations in a large pan-European population and to evaluate the diagnostic accuracy of the genetic markers. METHODS: Eligibility criteria required patients to be aged less than 19 years at the start of chemotherapy, which had to include cisplatin and/or carboplatin. Patients were assigned to three phenotype categories: no, minor and clinically relevant hearing loss. Fourteen variants in eleven candidate genes (ABCC3, OTOS, TPMT, SLC22A2, NFE2L2, SLC16A5, LRP2, GSTP1, SOD2, WFS1 and ACYP2) were investigated. Multinomial logistic regression was performed to model the relationship between genetic predictors and platinumototoxicity, adjusting for clinical risk factors. Additionally, measures of the diagnostic accuracy of the genetic markers were determined. RESULTS: 900 patients were included in this study. In the multinomial logistic regression, significant unique contributions were found from SLC22A2rs316019, the age at the start of platinum treatment, cranial radiation and the interaction term [platinum compound]∗[cumulative dose of cisplatin]. The predictive performance of the genetic markers was poor compared with the clinical risk factors. CONCLUSIONS: PanCareLIFE is the largest study of cisplatin-induced ototoxicity to date and confirmed a role for the polyspecific organic cation transporter SLC22A2. However, the predictive value of the current genetic candidate markers for clinical use is negligible, which puts the value of clinical factors for risk assessment of cisplatin-induced ototoxicity back into the foreground.
Authors: Nicolas Waespe; Sven Strebel; Tiago Nava; Chakradhara Rao S Uppugunduri; Denis Marino; Veneranda Mattiello; Maria Otth; Fabienne Gumy-Pause; André O Von Bueren; Frederic Baleydier; Luzius Mader; Adrian Spoerri; Claudia E Kuehni; Marc Ansari Journal: BMJ Open Date: 2022-01-24 Impact factor: 2.692
Authors: Matthew R Trendowski; Jessica L Baedke; Yadav Sapkota; Lois B Travis; Xindi Zhang; Omar El Charif; Heather E Wheeler; Wendy M Leisenring; Leslie L Robison; Melissa M Hudson; Lindsay M Morton; Kevin C Oeffinger; Rebecca M Howell; Gregory T Armstrong; Smita Bhatia; M Eileen Dolan Journal: Cancer Date: 2021-07-19 Impact factor: 6.860