Usefulness of current candidate genetic markers to identify childhood cancer patients at risk for platinum-induced ototoxicity: Results of the European PanCareLIFE cohort study.

Langer, Thorsten; Clemens, Eva; Broer, Linda; Maier, Lara; Uitterlinden, André G; de Vries, Andrica C H; van Grotel, Martine; Pluijm, Saskia F M; Binder, Harald; Mayer, Benjamin; von dem Knesebeck, Annika; Byrne, Julianne; van Dulmen-den Broeder, Eline; Crocco, Marco; Grabow, Desiree; Kaatsch, Peter; Kaiser, Melanie; Spix, Claudia; Kenborg, Line; Winther, Jeanette F; ... (2020). Usefulness of current candidate genetic markers to identify childhood cancer patients at risk for platinum-induced ototoxicity: Results of the European PanCareLIFE cohort study. European journal of cancer, 138, pp. 212-224. Elsevier 10.1016/j.ejca.2020.07.019

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Head Organs and Neurology (DKNS) > Clinic of Ear, Nose and Throat Disorders (ENT)
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 and Kompis, Martin

Subjects:

600 Technology > 610 Medicine & health
300 Social sciences, sociology & anthropology > 360 Social problems & social services

ISSN:

0959-8049

Publisher:

Elsevier

Language:

English

Submitter:

Doris Kopp Heim

Date Deposited:

20 Oct 2020 18:23

Last Modified:

21 Oct 2020 09:29

Publisher DOI:

10.1016/j.ejca.2020.07.019

PubMed ID:

32905960

Uncontrolled Keywords:

Adverse drug reaction Anti-neoplastic drugs Cancer survivors Childhood cancer Cisplatin: carboplatin Drug-induced ototoxicity Genetic markers Multicenter cohort study Pharmacogenetics

BORIS DOI:

10.7892/boris.147191

URI:

https://boris.unibe.ch/id/eprint/147191

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