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.
Citation
Meijer, A. J. M., Diepstraten, F. A., Langer, T., Broer, L., Domingo, I. K., Clemens, E., Uitterlinden, A. G., De Vries, A. C. H., Van Grotel, M., Vermeij, W. P., Ozinga, R. A., Binder, H., Byrne, J., Van Dulmen-den Broeder, E., Garrè, M. L., Grabow, D., Kaatsch, P., Kaiser, M., Kenborg, L., Winther, J. F., Rechnitzer, C., Hasle, H., Kepak, T., Kepakova, K., Tissing, W. J. E., Van Der Kooi, A. L. F., Kremer, L. C. M., Kruseova, J., Pluijm, S. M. F., Kuehni, C. E., Van Der Pal, H. J. H., Parfitt, R., Spix, C., Tillmanns, A., Deuster, D., Matulat, P., Calaminus, G., Hoetink, A. E., Elsner, S., Gebauer, J., Haupt, R., Lackner, H., Blattmann, C., Neggers, S. J. C. M. M., Rassekh, S. R., Wright, G. E. B., Brooks, B., Nagtegaal, A. P., Drögemöller, B. I., Ross, C. J. D., Bhavsar, A. P., Am Zehnhoff-Dinnesen, A. G., Carleton, B. C., Zolk, O., Van Den Heuvel-Eibrink, M. M., {the PanCareLIFE Consortium}, De Vries, A. C. H., Van Grotel, M., Van Dulmen-den Broeder, E., Van Der Kooi, A. L. F., Kremer, L. C. M., Van Der Pal, H. J. H., Calaminus, G., Hoetink, A. E., Van Den Heuvel-Eibrink, M. M., {and the CPNDS Consortium}, “TCERG1L allelic variation is associated with cisplatin-induced hearing loss in childhood cancer, a PanCareLIFE study,” npj Precision Oncology 5, 1(2021): 64, doi: 10.1038/s41698-021-00178-z