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JMIR Res Protoc. 2019 Mar 19;8(3):e11868. doi: 10.2196/11868.

Genetic Determinants of Ototoxicity During and After Childhood Cancer Treatment: Protocol for the PanCareLIFE Study.

Author information

1
Princess Maxima Center for Pediatric Oncology, Utrecht, Netherlands.
2
Department of Pediatric Hematology and Oncology, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, Netherlands.
3
Department of Internal Medicine, Erasmus Medical Center, Rotterdam, Netherlands.
4
Department of Pediatric Oncology, University Hospital for Children and Adolescents, Luebeck, Germany.
5
Department of Obstetrics and Gynecology, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, Netherlands.
6
Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.
7
Department of Paediatric Respiratory Medicine, University Children's Hospital, University of Bern, Bern, Switzerland.
8
Department of Neurooncology, Institute Giannina Gaslini, Genova, Italy.
9
Department of Paediatric Oncology, University Hospital Brno, Masaryk University, Brno, Czech Republic.
10
St. Anne's University Hospital Brno-International Clinical Research Center, Brno, Czech Republic.
11
Department of Pediatric Hemato-Oncology, Motol University Hospital Prague, Prague, Czech Republic.
12
Danish Cancer Society Research Center, Copenhagen, Denmark.
13
Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark.
14
Department of Pediatric Oncology, Academic Medical Center Amsterdam, Amsterdam, Netherlands.
15
Department of Pediatric Hematology and Oncology, VU Medical Center, Amsterdam, Netherlands.
16
Department of Pediatric Oncology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
17
Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
18
Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark.
19
German Childhood Cancer Registry, Institute of Medical Biostatistics, Epidemiology and Informatics, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
20
Department of Phoniatrics and Pedaudiology, University of Münster, Muenster, Germany.
21
Institute of Medical Biometry and Statistics, Faculty of Medicine and Medical Center, University of Freiburg, Freibug, Germany.
22
Division of Translational Therapeutics, Department of Pediatrics, British Columbia Children's Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada.
23
Boyne Research Institute, Drogheda, Ireland.
24
Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University Medical Center, Ulm, Germany.
#
Contributed equally

Abstract

BACKGROUND:

Survival rates after childhood cancer now reach nearly 80% in developed countries. However, treatments that lead to survival and cure can cause serious adverse effects with lifelong negative impacts on survivor quality of life. Hearing impairment is a common adverse effect in children treated with cisplatin-based chemotherapy or cranial radiotherapy. Ototoxicity can extend from high-tone hearing impairment to involvement of speech frequencies. Hearing impairment can impede speech and language and neurocognitive development. Although treatment-related risk factors for hearing loss following childhood cancer treatment have been identified, the individual variability in toxicity of adverse effects after similar treatment between childhood cancer patients suggests a role for genetic susceptibility. Currently, 12 candidate gene approach studies have been performed to identify polymorphisms predisposing to platinum-induced ototoxicity in children being treated for cancer. However, results were inconsistent and most studies were underpowered and/or lacked replication.

OBJECTIVE:

We describe the design of the PanCareLIFE consortium's work packages that address the genetic susceptibility of platinum-induced ototoxicity.

METHODS:

As a part of the PanCareLIFE study within the framework of the PanCare consortium, we addressed genetic susceptibility of treatment-induced ototoxicity during and after childhood cancer treatment in a large European cohort by a candidate gene approach and a genome-wide association screening.

RESULTS:

This study included 1124 survivors treated with cisplatin, carboplatin, or cranial radiotherapy for childhood cancer, resulting in the largest clinical European cohort assembled for this late effect to date. Within this large cohort we defined a group of 598 cisplatin-treated childhood cancer patients not confounded by cranial radiotherapy. The PanCareLIFE initiative provided, for the first time, a unique opportunity to confirm already identified determinants for hearing impairment during childhood cancer using a candidate gene approach and set up the first international genome-wide association study of cisplatin-induced direct ototoxicity in childhood cancer patients to identify novel allelic variants. Results will be validated in an independent replication cohort. Patient recruitment started in January 2015 and final inclusion was October 2017. We are currently performing the analyses and the first results are expected by the end of 2019 or the beginning of 2020.

CONCLUSIONS:

Genetic factors identified as part of this pan-European project, PanCareLIFE, may contribute to future risk prediction models that can be incorporated in future clinical trials of platinum-based therapies for cancer and may help with the development of prevention strategies.

INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID):

DERR1-10.2196/11868.

KEYWORDS:

GWAS; candidate genes; childhood cancer survivors; cisplatin; genetics; hearing loss; ototoxicity; polymorphisms

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