TY - JOUR
T1 - Genetic Determinants of Ototoxicity During and After Childhood Cancer Treatment
T2 - Protocol for the PanCareLIFE Study
AU - Clemens, Eva
AU - Meijer, Annelot Jm
AU - Broer, Linda
AU - Langer, Thorsten
AU - van der Kooi, Anne-Lotte Lf
AU - Uitterlinden, André G
AU - de Vries, Andrica
AU - Kuehni, Claudia E
AU - Garrè, Maria L
AU - Kepak, Tomas
AU - Kruseova, Jarmila
AU - Winther, Jeanette F
AU - Kremer, Leontien C
AU - van Dulmen-den Broeder, Eline
AU - Tissing, Wim Je
AU - Rechnitzer, Catherine
AU - Kenborg, Line
AU - Hasle, Henrik
AU - Grabow, Desiree
AU - Parfitt, Ross
AU - Binder, Harald
AU - Carleton, Bruce C
AU - Byrne, Julianne
AU - Kaatsch, Peter
AU - Am Zehnhoff-Dinnesen, Antoinette
AU - Zolk, Oliver
AU - van den Heuvel-Eibrink, Marry M
N1 - ©Eva Clemens, Annelot JM Meijer, Linda Broer, Thorsten Langer, Anne-Lotte LF van der Kooi, André G Uitterlinden, Andrica de Vries, Claudia E Kuehni, Maria L Garrè, Tomas Kepak, Jarmila Kruseova, Jeanette F Winther, Leontien C Kremer, Eline van Dulmen-den Broeder, Wim JE Tissing, Catherine Rechnitzer, Line Kenborg, Henrik Hasle, Desiree Grabow, Ross Parfitt, Harald Binder, Bruce C Carleton, Julianne Byrne, Peter Kaatsch, Antoinette am Zehnhoff-Dinnesen, Oliver Zolk, Marry M van den Heuvel-Eibrink. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 19.03.2019.
PY - 2019/3/19
Y1 - 2019/3/19
N2 - 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.
AB - 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.
KW - Candidate genes
KW - Childhood cancer survivors
KW - Cisplatin
KW - GWAS
KW - Genetics
KW - Hearing loss
KW - Ototoxicity
KW - Polymorphisms
UR - http://www.scopus.com/inward/record.url?scp=85067413444&partnerID=8YFLogxK
U2 - 10.2196/11868
DO - 10.2196/11868
M3 - Article
C2 - 30888333
SN - 1929-0748
VL - 8
SP - e11868
JO - JMIR research protocols
JF - JMIR research protocols
IS - 3
M1 - e11868
ER -