TY - JOUR
T1 - Genetic variation of cisplatin-induced ototoxicity in non-cranial-irradiated pediatric patients using a candidate gene approach
T2 - The International PanCareLIFE Study
AU - Clemens, Eva
AU - Broer, Linda
AU - Langer, Thorsten
AU - Uitterlinden, André G
AU - de Vries, Andrica C H
AU - van Grotel, Martine
AU - Pluijm, Saskia F M
AU - Binder, Harald
AU - Byrne, Julianne
AU - Broeder, Eline van Dulmen-den
AU - Crocco, Marco
AU - Grabow, Desiree
AU - Kaatsch, Peter
AU - Kaiser, Melanie
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 - Kuehni, Claudia E
AU - van der Pal, Heleen
AU - Parfitt, Ross
AU - Deuster, Dirk
AU - Matulat, Peter
AU - Spix, Claudia
AU - Tillmanns, Amelie
AU - Tissing, Wim J E
AU - Maier, Lara
AU - Am Zehnhoff-Dinnesen, Antoinette
AU - Zolk, Oliver
AU - van den Heuvel-Eibrink, Marry M
AU - PanCareLIFE consortium
PY - 2020/4
Y1 - 2020/4
N2 - Ototoxicity is a common side effect of platinum treatment and manifests as irreversible, high-frequency sensorineural hearing loss. Genetic association studies have suggested a role for SNPs in genes related to the disposition of cisplatin or deafness. In this study, 429 pediatric patients that were treated with cisplatin were genotyped for 10 candidate SNPs. Logistic regression analyses revealed that younger age at treatment (≤5 years vs >15 years: OR: 9.1; 95% CI: 3.8-21.5; P = 5.6 × 10-7) and higher cumulative dose of cisplatin (>450 vs ≤300 mg/m2: OR: 2.4; 95% CI: 1.3-4.6; P = 0.007) confer a significant risk of ototoxicity. Of the SNPs investigated, none of them were significantly associated with an increase of ototoxicity. In the meta-analysis, ACYP2 rs1872328 (OR: 3.94; 95% CI: 1.04-14.03; P = 0.04) and SLC22A2 rs316019 (OR: 1.46; 95% CI: 1.07-2.00; P = 0.02) were associated with ototoxicity. In order to increase the understanding of the association between SNPs and ototoxicity, we propose a polygenic model, which takes into account multiple interacting genes of the cisplatin pathway that together confer an increased risk of ototoxicity.
AB - Ototoxicity is a common side effect of platinum treatment and manifests as irreversible, high-frequency sensorineural hearing loss. Genetic association studies have suggested a role for SNPs in genes related to the disposition of cisplatin or deafness. In this study, 429 pediatric patients that were treated with cisplatin were genotyped for 10 candidate SNPs. Logistic regression analyses revealed that younger age at treatment (≤5 years vs >15 years: OR: 9.1; 95% CI: 3.8-21.5; P = 5.6 × 10-7) and higher cumulative dose of cisplatin (>450 vs ≤300 mg/m2: OR: 2.4; 95% CI: 1.3-4.6; P = 0.007) confer a significant risk of ototoxicity. Of the SNPs investigated, none of them were significantly associated with an increase of ototoxicity. In the meta-analysis, ACYP2 rs1872328 (OR: 3.94; 95% CI: 1.04-14.03; P = 0.04) and SLC22A2 rs316019 (OR: 1.46; 95% CI: 1.07-2.00; P = 0.02) were associated with ototoxicity. In order to increase the understanding of the association between SNPs and ototoxicity, we propose a polygenic model, which takes into account multiple interacting genes of the cisplatin pathway that together confer an increased risk of ototoxicity.
U2 - 10.1038/s41397-019-0113-1
DO - 10.1038/s41397-019-0113-1
M3 - Journal article
C2 - 31666714
SN - 1470-269X
VL - 20
SP - 294
EP - 305
JO - The pharmacogenomics journal
JF - The pharmacogenomics journal
IS - 2
ER -