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

Clemens, Eva; Meijer, Annelot Jm; Broer, Linda; Langer, Thorsten; van der Kooi, Anne-Lotte Lf; Uitterlinden, André G; de Vries, Andrica; Kuehni, Claudia E; Garrè, Maria L; Kepak, Tomas; Kruseova, Jarmila; Winther, Jeanette F; Kremer, Leontien C; van Dulmen-den Broeder, Eline; Tissing, Wim Je; Rechnitzer, Catherine; Kenborg, Line; Hasle, Henrik; Grabow, Desiree; Parfitt, Ross; ... (2019). Genetic Determinants of Ototoxicity During and After Childhood Cancer Treatment: Protocol for the PanCareLIFE Study. JMIR research protocols, 8(3), e11868. JMIR Publications 10.2196/11868

[img]
Preview
Text
Clemens JMIRResProtoc 2019.pdf - Published Version
Available under License Creative Commons: Attribution (CC-BY).

Download (779kB) | Preview

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.

Item Type:

Journal Article (Further Contribution)

Division/Institute:

04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Paediatric Medicine
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Social and Preventive Medicine (ISPM)

UniBE Contributor:

Kühni, Claudia

Subjects:

600 Technology > 610 Medicine & health
300 Social sciences, sociology & anthropology > 360 Social problems & social services
000 Computer science, knowledge & systems > 020 Library & information sciences

ISSN:

1929-0748

Publisher:

JMIR Publications

Language:

English

Submitter:

Andrea Flükiger-Flückiger

Date Deposited:

27 Mar 2019 11:39

Last Modified:

06 Jan 2020 10:54

Publisher DOI:

10.2196/11868

PubMed ID:

30888333

Uncontrolled Keywords:

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

BORIS DOI:

10.7892/boris.129207

URI:

https://boris.unibe.ch/id/eprint/129207

Actions (login required)

Edit item Edit item
Provide Feedback