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Usefulness of current candidate genetic markers to identify childhood cancer patients at risk for platinum-induced ototoxicity: Results of the European PanCareLIFE cohort study
T. Langer, E. Clemens, L. Broer, L. Maier, AG. Uitterlinden, ACH. de Vries, M. van Grotel, SFM. Pluijm, H. Binder, B. Mayer, A. von dem Knesebeck, J. Byrne, E. van Dulmen-den Broeder, M. Crocco, D. Grabow, P. Kaatsch, M. Kaiser, C. Spix, L....
Jazyk angličtina Země Velká Británie
Typ dokumentu časopisecké články, multicentrická studie, práce podpořená grantem
- MeSH
- cisplatina škodlivé účinky MeSH
- dítě MeSH
- farmakogenomické testování MeSH
- farmakogenomické varianty * MeSH
- genetická predispozice k nemoci MeSH
- genetické asociační studie MeSH
- hodnocení rizik MeSH
- jednonukleotidový polymorfismus * MeSH
- karboplatina škodlivé účinky MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- nádory farmakoterapie MeSH
- novorozenec MeSH
- ototoxicita MeSH
- percepční nedoslýchavost chemicky indukované genetika patofyziologie MeSH
- předškolní dítě MeSH
- přežívající onkologičtí pacienti * MeSH
- prospektivní studie MeSH
- protinádorové látky škodlivé účinky MeSH
- průřezové studie MeSH
- retrospektivní studie MeSH
- rizikové faktory MeSH
- sluch účinky léků MeSH
- transportér organických kationtů 2 genetika MeSH
- věk při počátku nemoci MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- novorozenec MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Evropa MeSH
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.
Aarhus University Hospital Department of Pediatrics Aarhus University Hospital Aarhus Denmark
Boyne Research Institute Drogheda Ireland
Danish Cancer Society Research Center Childhood Cancer Research Group Copenhagen Denmark
Department of Children Hemato Oncology Motol University Hospital Prague Prague Czech Republic
Department of Clinical Medicine Faculty of Health Aarhus University Aarhus Denmark
Department of Internal Medicine Erasmus Medical Center Rotterdam the Netherlands
Department of Neurooncology Istituto Giannina Gaslini Genova Italy
Department of Obstetrics and Gynecology Erasmus MC Sophia Children's Hospital the Netherlands
Department of Otolaryngology Head and Neck Surgery Inselspital University of Berne Switzerland
Department of Pediatric Hematology and Oncology VU Medical Center Amsterdam the Netherlands
Department of Pediatric Oncology Academic Medical Center Amsterdam Amsterdam the Netherlands
Department of Pediatric Oncology Erasmus MC Sophia Children's Hospital Rotterdam the Netherlands
Hospital for Children and Adolescents University of Erlangen Nuremberg Erlangen Germany
Institute for Social Medicine and Epidemiology University of Lübeck Lübeck Germany
Institute of Epidemiology and Medical Biometry University of Ulm Ulm Germany
Institute of Social and Preventive Medicine University of Bern Bern Switzerland
International Clinical Research Center Brno Czech Republic
Paediatric Oncology Dept of Paediatrics Inselspital University of Bern Switzerland
Princess Máxima Center for Pediatric Oncology Utrecht the Netherlands
Citace poskytuje Crossref.org
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- $a Langer, Thorsten $u Department of Pediatric Oncology and Hematology, University Hospital for Children and Adolescents, Lübeck, Germany
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- $a Usefulness of current candidate genetic markers to identify childhood cancer patients at risk for platinum-induced ototoxicity: Results of the European PanCareLIFE cohort study / $c T. Langer, E. Clemens, L. Broer, L. Maier, AG. Uitterlinden, ACH. de Vries, M. van Grotel, SFM. Pluijm, H. Binder, B. Mayer, A. von dem Knesebeck, J. Byrne, E. van Dulmen-den Broeder, M. Crocco, D. Grabow, P. Kaatsch, M. Kaiser, C. Spix, L. Kenborg, JF. Winther, C. Rechnitzer, H. Hasle, T. Kepak, AF. van der Kooi, LC. Kremer, J. Kruseova, S. Bielack, B. Sorg, S. Hecker-Nolting, CE. Kuehni, M. Ansari, M. Kompis, H. van der Pal, R. Parfitt, D. Deuster, P. Matulat, A. Tillmanns, WJE. Tissing, JD. Beck, S. Elsner, A. Am Zehnhoff-Dinnesen, MM. van den Heuvel-Eibrink, O. Zolk, PanCareLIFE consortium
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- $a 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.
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