TCERG1L allelic variation is associated with cisplatin-induced hearing loss in childhood cancer, a PanCareLIFE study
Annelot J. M. Meijer, Franciscus A. Diepstraten, Thorsten Langer, Linda Broer, Ivan K. Domingo, Eva Clemens, André G. Uitterlinden, Andrica C. H. de Vries, Martine van Grotel, Wilbert P. Vermeij, Rutger A. Ozinga, Harald Binder, Julianne Byrne, Eline van Dulmen‐den Broeder, Maria Luisa Garrè, Desiree Grabow, Peter Kaatsch, Melanie Kaiser, Line Kenborg, Jeanette Falck Winther, Catherine Rechnitzer, Henrik Hasle, Tomáš Kepák, Kateřina Kepáková, Wim J. E. Tissing, Anne-Lotte van der Kooi, Leontien C.M. Kremer, Jarmila Kruseová, Saskia M.F. Pluijm, Claudia E. Kuehni, Helena J. H. van der Pal, Ross Parfitt, Claudia Spix, Amélie Tillmanns, Dirk Deuster, Peter Matulat, Gabriele Calaminus, Alex E. Hoetink, Susanne Elsner, Judith Gebauer, Riccardo Haupt, Herwig Lackner, Claudia Blattmann, Sebastian Neggers, Shahrad R. Rassekh, Galen E.B. Wright, Beth Brooks, A. Paul Nagtegaal, Britt I. Drögemöller, Colin J.D. Ross, Amit P. Bhavsar, Antoinette Gertrud am Zehnhoff-Dinnesen, Bruce Carleton, Oliver Zolk, Marry M. van den Heuvel‐Eibrink, Andrica C. H. de Vries, Martine van Grotel, Eline van Dulmen‐den Broeder, Anne-Lotte van der Kooi, Leontien C.M. Kremer, Helena J. H. van der Pal, Gabriele Calaminus, Alex E. Hoetink, Marry M. van den Heuvel‐Eibrink
Abstract
Abstract In children with cancer, the heterogeneity in ototoxicity occurrence after similar treatment suggests a role for genetic susceptibility. Using a genome-wide association study (GWAS) approach, we identified a genetic variant in TCERG1L (rs893507) to be associated with hearing loss in 390 non-cranial irradiated, cisplatin-treated children with cancer. These results were replicated in two independent, similarly treated cohorts ( n = 192 and 188, respectively) (combined cohort: P = 5.3 × 10 −10 , OR 3.11, 95% CI 2.2–4.5). Modulating TCERG1L expression in cultured human cells revealed significantly altered cellular responses to cisplatin-induced cytokine secretion and toxicity. These results contribute to insights into the genetic and pathophysiological basis of cisplatin-induced ototoxicity.