Megalin genetic polymorphisms and individual sensitivity to the ototoxic effect of cisplatin.
Ototoxicity and nephrotoxicity are dose-limiting side effects of cisplatin. Megalin, a member of the low-density lipoprotein receptor family, is highly expressed in renal proximal tubular cells and marginal cells of the stria vascularis of the inner ear - tissues, which accumulate high levels of platinum-DNA adducts. On the assumption that the mechanisms of cisplatin-induced nephro- and ototoxicity involve megalin we analyzed the incidence of the non-synonymous single nucleotide polymorphisms (SNP) rs2075252 and rs4668123 in 25 patients who developed a distinct hearing loss during cisplatin therapy and in 25 patients without hearing impairment after cisplatin therapy. We found no association between cisplatin-induced ototoxicity and any allele of rs4668123 but observed a higher frequency of the A-allele of rs2075252 in the group with hearing impairment than in the group with normal hearing after cisplatin therapy (0.32 versus 0.14) (chi(2)=5.83, P<0.02; odds ratio: 3.45; 95% confidence interval: 1.11-11.2) indicating that SNPs at the megalin gene might impact the individual susceptibility against cisplatin-induced ototoxicity.
Riedemann
L
L
Department of Pediatric Hematology and Oncology, University Children's Hospital, Münster, Germany. A.am.Zehnhoff.Dinnesen@uni-muenster.de
Lanvers
C
C
Deuster
D
D
Peters
U
U
Boos
J
J
Jürgens
H
H
am Zehnhoff-Dinnesen
A
A
D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001301:Audiometry, Pure-Tone; D002648:Child; D002675:Child, Preschool; D002945:Cisplatin / Q000009:adverse effects* / Q000627:therapeutic use; D005260:Female; D005838:Genotype; D006311:Hearing Disorders / Q000139:chemically induced* / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000235:genetics*; D008297:Male; D009369:Neoplasms / Q000150:complications / Q000188:drug therapy; D011110:Polymorphism, Genetic / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000970:Antineoplastic Agents; D026561:Low Density Lipoprotein Receptor-Related Protein-2; D002945:Cisplatin