title: Human OCT2 variant c.808G>T confers protection effect against cisplatin-induced ototoxicity.
abstract: OBJECTIVE
  Assuming that genetic variants of the SLC22A2 and SLC31A1 transporter affect patients' susceptibility to cisplatin-induced ototoxicity, we compared the distribution of 11 SLC22A2 variants and the SLC31A1 variant rs10981694 between patients with and without cisplatin-induced ototoxicity.
  
  
  METHODS
  Genotyping was performed in 64 pediatric patients and significant findings were re-evaluated in 66 adults.
  
  
  RESULTS
  The SLC22A2 polymorphism rs316019 (c.808G>T; Ser270Ala) was significantly associated with protection from cisplatin-induced ototoxicity in the pediatric (p = 0.022) and the adult cohort (p = 0.048; both: Fisher's exact test). This result was confirmed by multiple logistic regression analysis accounting for age which was identified as a relevant factor for ototoxicity as well (rs316019: OR [G/T vs G/G] = 0.12, p = 0.009; age: OR [per year]: 0.84, p = 0.02).
  
  
  CONCLUSIONS
  These results identified rs316019 as potential pharmacogenomic marker for cisplatin-induced ototoxicity and point to a critical role of SLC22A2 for cisplatin transport in humans and its contribution to the organ specific side effects of this drug. Original submitted 17 September 2014; Revision submitted 19 December 2014.
authors.affiliation: Department of Pediatric Hematology & Oncology, University Children's Hospital of Muenster, Muenster, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Lanvers-Kaminsky
authors.forename: Jason A
authors.initials: JA
authors.lastname: Sprowl
authors.forename: Ingrid
authors.initials: I
authors.lastname: Malath
authors.forename: Dirk
authors.initials: D
authors.lastname: Deuster
authors.forename: Maria
authors.initials: M
authors.lastname: Eveslage
authors.forename: Eberhard
authors.initials: E
authors.lastname: Schlatter
authors.forename: Ron Hj
authors.initials: RH
authors.lastname: Mathijssen
authors.forename: Joachim
authors.initials: J
authors.lastname: Boos
authors.forename: Heribert
authors.initials: H
authors.lastname: Jürgens
authors.forename: Antionette G
authors.initials: AG
authors.lastname: Am Zehnhoff-Dinnesen
authors.forename: Alex
authors.initials: A
authors.lastname: Sparreboom
authors.forename: Giuliano
authors.initials: G
authors.lastname: Ciarimboli
mesh_terms: D000293:Adolescent; D000328:Adult; D027682:Cation Transport Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects*; D000079923:Copper Transporter 1; D064420:Drug-Related Side Effects and Adverse Reactions / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D027701:Organic Cation Transport Proteins / Q000235:genetics*; D000075102:Organic Cation Transporter 2; D020641:Polymorphism, Single Nucleotide
chemical_list: D027682:Cation Transport Proteins; D000079923:Copper Transporter 1; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; C491013:SLC22A2 protein, human; C490079:SLC31A1 protein, human; D002945:Cisplatin
keywords: SLC22A2; SLC31A1; cisplatin; ototoxicity; polymorphism
references.citation: J Neurosci. 2010 Jul 14;30(28):9500-9
references.pmid: 20631178
references.citation: Pediatr Blood Cancer. 2012 Jul 15;59(1):144-8
references.pmid: 22431292
references.citation: Food Chem Toxicol. 2012 Jul;50(7):2289-93
references.pmid: 22525860
references.citation: Int J Radiat Oncol Biol Phys. 2007 Aug 1;68(5):1320-5
references.pmid: 17418969
references.citation: Pediatr Hematol Oncol. 2007 Sep;24(6):403-8
references.pmid: 17710657
references.citation: Pharmacogenomics J. 2008 Feb;8(1):23-8
references.pmid: 17457342
references.citation: Clin Cancer Res. 2008 Jun 15;14(12):3875-80
references.pmid: 18559608
references.citation: Pediatr Blood Cancer. 2009 Mar;52(3):387-91
references.pmid: 19061216
references.citation: Drug Metab Dispos. 2009 Jun;37(6):1312-8
references.pmid: 19251820
references.citation: Clin Pharmacol Ther. 2009 Oct;86(4):396-402
references.pmid: 19625999
references.citation: Pharmacogenomics J. 2009 Oct;9(5):347-53
references.pmid: 19434073
references.citation: Nat Genet. 2009 Dec;41(12):1345-9
references.pmid: 19898482
references.citation: Am J Pathol. 2010 Mar;176(3):1169-80
references.pmid: 20110413
references.citation: J Clin Oncol. 2010 Apr 1;28(10):1788-95
references.pmid: 20194861
references.citation: J Clin Oncol. 2012 Jul 1;30(19):2408-17
references.pmid: 22547603
references.citation: Lung Cancer. 2012 Aug;77(2):438-42
references.pmid: 22516052
references.citation: Pediatr Blood Cancer. 2013 Feb;60(2):287-92
references.pmid: 23002030
references.citation: J Pediatr Hematol Oncol. 2013 May;35(4):e138-43
references.pmid: 23274376
references.citation: Mol Pharmacol. 2013 Jun;83(6):1237-46
references.pmid: 23543413
references.citation: Clin Pharmacol Ther. 2013 Aug;94(2):243-51
references.pmid: 23588304
references.citation: Clin Pharmacol Ther. 2013 Aug;94(2):252-9
references.pmid: 23820299
references.citation: Cochrane Database Syst Rev. 2013;10:CD008944
references.pmid: 24101439
references.citation: J Clin Oncol. 2014 Feb 20;32(6):527-34
references.pmid: 24419114
references.citation: Anticancer Drugs. 2000 Sep;11(8):639-43
references.pmid: 11081456
references.citation: Pharmacogenetics. 2002 Jul;12(5):395-405
references.pmid: 12142729
references.citation: Cancer Res. 2002 Nov 15;62(22):6559-65
references.pmid: 12438251
references.citation: Br J Cancer. 2003 Apr 22;88(8):1199-206
references.pmid: 12698184
references.citation: Cancer Treat Rep. 1982 Dec;66(12):2013-20
references.pmid: 6890409
references.citation: Br J Cancer. 1990 Jun;61(6):927-31
references.pmid: 2372498
references.citation: Med Pediatr Oncol. 1991;19(4):295-300
references.pmid: 2056973
references.citation: Br J Cancer. 1998 Apr;77(8):1355-62
references.pmid: 9579846
references.citation: Eur J Cancer. 2004 Nov;40(16):2445-51
references.pmid: 15519518
references.citation: Pediatr Blood Cancer. 2004 Dec;43(7):780-4
references.pmid: 15390300
references.citation: J Clin Oncol. 2005 Dec 1;23(34):8588-96
references.pmid: 16314621
references.citation: J Clin Oncol. 2006 Apr 1;24(10):1499-506
references.pmid: 16574999
references.citation: Pediatr Blood Cancer. 2006 Aug;47(2):183-93
references.pmid: 16302218
references.citation: J Clin Oncol. 2007 Feb 20;25(6):708-14
references.pmid: 17228018
references.citation: Drug Metab Dispos. 2007 Apr;35(4):667-75
references.pmid: 17220237
references.citation: J Clin Oncol. 2007 Apr 1;25(10):1190-5
references.pmid: 17401008
references.citation: HNO. 2007 Apr;55(4):299-306
references.pmid: 16437215