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

Thorsten Langer; Eva Clemens; Linda Broer; Lara Maier; André G Uitterlinden; Andrica C H de Vries; Martine van Grotel; Saskia F M Pluijm; Harald Binder; Benjamin Mayer; Annika von dem Knesebeck; Julianne Byrne; Eline van Dulmen-den Broeder; Marco Crocco; Desiree Grabow; Peter Kaatsch; Melanie Kaiser; Claudia Spix; Line Kenborg; Jeanette F Winther; Catherine Rechnitzer; Henrik Hasle; Tomas Kepak; Anne-Lotte F van der Kooi; Leontien C Kremer; Jarmila Kruseova; Stefan Bielack; Benjamin Sorg; Stefanie Hecker-Nolting; Claudia E Kuehni; Marc Ansari; Martin Kompis; Heleen van der Pal; Ross Parfitt; Dirk Deuster; Peter Matulat; Amelie Tillmanns; Wim J E Tissing; Jörn D Beck; Susanne Elsner; Antoinette Am Zehnhoff-Dinnesen; Marry M van den Heuvel-Eibrink; Oliver Zolk; PanCareLIFE consortium

doi:10.1016/j.ejca.2020.07.019

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

Thorsten Langer, Eva Clemens, Linda Broer, Lara Maier, André G Uitterlinden, Andrica C H de Vries, Martine van Grotel, Saskia F M Pluijm, Harald Binder, Benjamin Mayer, Annika von dem Knesebeck, Julianne Byrne, Eline van Dulmen-den Broeder, Marco Crocco, Desiree Grabow, Peter Kaatsch, Melanie Kaiser, Claudia Spix, Line Kenborg, Jeanette F WintherCatherine Rechnitzer, Henrik Hasle, Tomas Kepak, Anne-Lotte F van der Kooi, Leontien C Kremer, Jarmila Kruseova, Stefan Bielack, Benjamin Sorg, Stefanie Hecker-Nolting, Claudia E Kuehni, Marc Ansari, Martin Kompis, Heleen van der Pal, Ross Parfitt, Dirk Deuster, Peter Matulat, Amelie Tillmanns, Wim J E Tissing, Jörn D Beck, Susanne Elsner, Antoinette Am Zehnhoff-Dinnesen, Marry M van den Heuvel-Eibrink, Oliver Zolk, PanCareLIFE consortium

Department of Paediatrics and Adolescent Medicine

Abstract

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.

Original language	English
Journal	European Journal of Cancer
Volume	138
Pages (from-to)	212-224
Number of pages	13
ISSN	0959-8049
DOIs	https://doi.org/10.1016/j.ejca.2020.07.019
Publication status	Published - Oct 2020

Keywords

Adolescent
Age of Onset
Antineoplastic Agents/adverse effects
Cancer Survivors
Carboplatin/adverse effects
Child
Child, Preschool
Cisplatin/adverse effects
Cross-Sectional Studies
Europe
Female
Genetic Association Studies
Genetic Predisposition to Disease
Hearing/drug effects
Hearing Loss, Sensorineural/chemically induced
Humans
Infant
Infant, Newborn
Male
Neoplasms/drug therapy
Organic Cation Transporter 2/genetics
Ototoxicity
Pharmacogenomic Testing
Pharmacogenomic Variants
Polymorphism, Single Nucleotide
Prospective Studies
Retrospective Studies
Risk Assessment
Risk Factors

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10.1016/j.ejca.2020.07.019

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Langer, T., Clemens, E., Broer, L., Maier, L., Uitterlinden, A. G., de Vries, A. C. H., van Grotel, M., Pluijm, S. F. M., Binder, H., Mayer, B., von dem Knesebeck, A., Byrne, J., van Dulmen-den Broeder, E., Crocco, M., Grabow, D., Kaatsch, P., Kaiser, M., Spix, C., Kenborg, L., ... PanCareLIFE consortium (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, 212-224. https://doi.org/10.1016/j.ejca.2020.07.019

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 et al.
In: European Journal of Cancer, Vol. 138, 10.2020, p. 212-224.

Research output: Contribution to journal › Journal article › Research › peer-review

Langer, T, Clemens, E, Broer, L, Maier, L, Uitterlinden, AG, de Vries, ACH, van Grotel, M, Pluijm, SFM, Binder, H, Mayer, B, von dem Knesebeck, A, Byrne, J, van Dulmen-den Broeder, E, Crocco, M, Grabow, D, Kaatsch, P, Kaiser, M, Spix, C, Kenborg, L, Winther, JF, Rechnitzer, C, Hasle, H, Kepak, T, van der Kooi, A-LF, Kremer, LC, Kruseova, J, Bielack, S, Sorg, B, Hecker-Nolting, S, Kuehni, CE, Ansari, M, Kompis, M, van der Pal, H, Parfitt, R, Deuster, D, Matulat, P, Tillmanns, A, Tissing, WJE, Beck, JD, Elsner, S, Am Zehnhoff-Dinnesen, A, van den Heuvel-Eibrink, MM, Zolk, O & PanCareLIFE consortium 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, vol. 138, pp. 212-224. https://doi.org/10.1016/j.ejca.2020.07.019

@article{ccac931a29794d239ed2566e5f5109f5,

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

abstract = "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.",

keywords = "Adolescent, Age of Onset, Antineoplastic Agents/adverse effects, Cancer Survivors, Carboplatin/adverse effects, Child, Child, Preschool, Cisplatin/adverse effects, Cross-Sectional Studies, Europe, Female, Genetic Association Studies, Genetic Predisposition to Disease, Hearing/drug effects, Hearing Loss, Sensorineural/chemically induced, Humans, Infant, Infant, Newborn, Male, Neoplasms/drug therapy, Organic Cation Transporter 2/genetics, Ototoxicity, Pharmacogenomic Testing, Pharmacogenomic Variants, Polymorphism, Single Nucleotide, Prospective Studies, Retrospective Studies, Risk Assessment, Risk Factors",

author = "Thorsten Langer and Eva Clemens and Linda Broer and Lara Maier and Uitterlinden, {Andr{\'e} G} and {de Vries}, {Andrica C H} and {van Grotel}, Martine and Pluijm, {Saskia F M} and Harald Binder and Benjamin Mayer and {von dem Knesebeck}, Annika and Julianne Byrne and {van Dulmen-den Broeder}, Eline and Marco Crocco and Desiree Grabow and Peter Kaatsch and Melanie Kaiser and Claudia Spix and Line Kenborg and Winther, {Jeanette F} and Catherine Rechnitzer and Henrik Hasle and Tomas Kepak and {van der Kooi}, {Anne-Lotte F} and Kremer, {Leontien C} and Jarmila Kruseova and Stefan Bielack and Benjamin Sorg and Stefanie Hecker-Nolting and Kuehni, {Claudia E} and Marc Ansari and Martin Kompis and {van der Pal}, Heleen and Ross Parfitt and Dirk Deuster and Peter Matulat and Amelie Tillmanns and Tissing, {Wim J E} and Beck, {J{\"o}rn D} and Susanne Elsner and {Am Zehnhoff-Dinnesen}, Antoinette and {van den Heuvel-Eibrink}, {Marry M} and Oliver Zolk and {PanCareLIFE consortium}",

year = "2020",

month = oct,

doi = "10.1016/j.ejca.2020.07.019",

language = "English",

volume = "138",

pages = "212--224",

journal = "European Journal of Cancer",

issn = "0959-8049",

publisher = "Pergamon",

}

TY - JOUR

T1 - Usefulness of current candidate genetic markers to identify childhood cancer patients at risk for platinum-induced ototoxicity

T2 - Results of the European PanCareLIFE cohort study

AU - Langer, Thorsten

AU - Clemens, Eva

AU - Broer, Linda

AU - Maier, Lara

AU - Uitterlinden, André G

AU - de Vries, Andrica C H

AU - van Grotel, Martine

AU - Pluijm, Saskia F M

AU - Binder, Harald

AU - Mayer, Benjamin

AU - von dem Knesebeck, Annika

AU - Byrne, Julianne

AU - van Dulmen-den Broeder, Eline

AU - Crocco, Marco

AU - Grabow, Desiree

AU - Kaatsch, Peter

AU - Kaiser, Melanie

AU - Spix, Claudia

AU - Kenborg, Line

AU - Winther, Jeanette F

AU - Rechnitzer, Catherine

AU - Hasle, Henrik

AU - Kepak, Tomas

AU - van der Kooi, Anne-Lotte F

AU - Kremer, Leontien C

AU - Kruseova, Jarmila

AU - Bielack, Stefan

AU - Sorg, Benjamin

AU - Hecker-Nolting, Stefanie

AU - Kuehni, Claudia E

AU - Ansari, Marc

AU - Kompis, Martin

AU - van der Pal, Heleen

AU - Parfitt, Ross

AU - Deuster, Dirk

AU - Matulat, Peter

AU - Tillmanns, Amelie

AU - Tissing, Wim J E

AU - Beck, Jörn D

AU - Elsner, Susanne

AU - Am Zehnhoff-Dinnesen, Antoinette

AU - van den Heuvel-Eibrink, Marry M

AU - Zolk, Oliver

AU - PanCareLIFE consortium

PY - 2020/10

Y1 - 2020/10

N2 - 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.

AB - 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.

KW - Adolescent

KW - Age of Onset

KW - Antineoplastic Agents/adverse effects

KW - Cancer Survivors

KW - Carboplatin/adverse effects

KW - Child

KW - Child, Preschool

KW - Cisplatin/adverse effects

KW - Cross-Sectional Studies

KW - Europe

KW - Female

KW - Genetic Association Studies

KW - Genetic Predisposition to Disease

KW - Hearing/drug effects

KW - Hearing Loss, Sensorineural/chemically induced

KW - Humans

KW - Infant

KW - Infant, Newborn

KW - Male

KW - Neoplasms/drug therapy

KW - Organic Cation Transporter 2/genetics

KW - Ototoxicity

KW - Pharmacogenomic Testing

KW - Pharmacogenomic Variants

KW - Polymorphism, Single Nucleotide

KW - Prospective Studies

KW - Retrospective Studies

KW - Risk Assessment

KW - Risk Factors

U2 - 10.1016/j.ejca.2020.07.019

DO - 10.1016/j.ejca.2020.07.019

M3 - Journal article

C2 - 32905960

SN - 0959-8049

VL - 138

SP - 212

EP - 224

JO - European Journal of Cancer

JF - European Journal of Cancer

ER -

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

Abstract

Keywords

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