Usefulness of current candidate genetic markers to identify childhood cancer patients at risk for platinum-induced ototoxicity: Results of the European PanCareLIFE cohort study
Language English Country England, Great Britain Media print-electronic
Document type Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't
PubMed
32905960
DOI
10.1016/j.ejca.2020.07.019
PII: S0959-8049(20)30418-4
Knihovny.cz E-resources
- Keywords
- Adverse drug reaction, Anti-neoplastic drugs, Cancer survivors, Childhood cancer, Cisplatin: carboplatin, Drug-induced ototoxicity, Genetic markers, Multicenter cohort study, Pharmacogenetics,
- MeSH
- Cisplatin adverse effects MeSH
- Child MeSH
- Pharmacogenomic Testing MeSH
- Pharmacogenomic Variants * MeSH
- Genetic Predisposition to Disease MeSH
- Genetic Association Studies MeSH
- Risk Assessment MeSH
- Polymorphism, Single Nucleotide * MeSH
- Carboplatin adverse effects MeSH
- Infant MeSH
- Humans MeSH
- Adolescent MeSH
- Neoplasms drug therapy MeSH
- Infant, Newborn MeSH
- Ototoxicity MeSH
- Hearing Loss, Sensorineural chemically induced genetics physiopathology MeSH
- Child, Preschool MeSH
- Cancer Survivors * MeSH
- Prospective Studies MeSH
- Antineoplastic Agents adverse effects MeSH
- Cross-Sectional Studies MeSH
- Retrospective Studies MeSH
- Risk Factors MeSH
- Hearing drug effects MeSH
- Organic Cation Transporter 2 genetics MeSH
- Age of Onset MeSH
- Check Tag
- Child MeSH
- Infant MeSH
- Humans MeSH
- Adolescent MeSH
- Male MeSH
- Infant, Newborn MeSH
- Child, Preschool MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
- Research Support, Non-U.S. Gov't MeSH
- Geographicals
- Europe MeSH
- Names of Substances
- Cisplatin MeSH
- Carboplatin MeSH
- Antineoplastic Agents MeSH
- SLC22A2 protein, human MeSH Browser
- Organic Cation Transporter 2 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 Internal Medicine Erasmus Medical Center Rotterdam the Netherlands
Department of Neurooncology Istituto Giannina Gaslini Genova Italy
Department of Otolaryngology Head and Neck Surgery Inselspital University of Berne Switzerland
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
Princess Máxima Center for Pediatric Oncology Utrecht the Netherlands
References provided by Crossref.org
