title: Germline single nucleotide polymorphisms associated with response of urothelial carcinoma to platinum-based therapy: the role of the host.
abstract: BACKGROUND
  Variations in urothelial carcinoma (UC) response to platinum chemotherapy are common and frequently attributed to genetic and epigenetic variations of somatic DNA. We hypothesized that variations in germline DNA may contribute to UC chemosensitivity.
  
  
  METHODS
  DNA from 210 UC patients treated with platinum-based chemotherapy was genotyped for 80 single nucleotide polymorphisms (SNPs). Logistic regression was used to examine the association between SNPs and response, and a multivariable predictive model was created. Significant SNPs were combined to form a SNP score predicting response. Eleven UC cell lines were genotyped as validation.
  
  
  RESULTS
  Six SNPs were significantly associated with 101 complete or partial responses (48%). Four SNPs retained independence association and were incorporated into a response prediction model. Each additional risk allele was associated with a nearly 50% decrease in odds of response [odds ratio (OR) = 0.51, 95% confidence interval 0.39-0.65, P = 1.05 × 10(-7)). The bootstrap-adjusted area under the curves of this model was greater than clinical prognostic factors alone (0.78 versus 0.64). The SNP score showed a positive trend with chemosensitivity in cell lines (P = 0.115).
  
  
  CONCLUSIONS
  Genetic variants associated with response of UC to platinum-based therapy were identified in germline DNA. A model using these genetic variants may predict response to chemotherapy better than clinical factors alone.
authors.affiliation: Department of Medical Oncology and Cancer Genetics, Mater Hospital and St. James's Hospital, Dublin 7, Ireland. daithig@gmail.com
authors.forename: D J
authors.initials: DJ
authors.lastname: Gallagher
authors.forename: J
authors.initials: J
authors.lastname: Vijai
authors.forename: R J
authors.initials: RJ
authors.lastname: Hamilton
authors.forename: I
authors.initials: I
authors.lastname: Ostrovnaya
authors.forename: G
authors.initials: G
authors.lastname: Iyer
authors.forename: I R
authors.initials: IR
authors.lastname: Garcia-Grossman
authors.forename: P H
authors.initials: PH
authors.lastname: Kim
authors.forename: J A
authors.initials: JA
authors.lastname: Przybylo
authors.forename: S
authors.initials: S
authors.lastname: Alanee
authors.forename: J C
authors.initials: JC
authors.lastname: Riches
authors.forename: A M
authors.initials: AM
authors.lastname: Regazzi
authors.forename: M I
authors.initials: MI
authors.lastname: Milowsky
authors.forename: K
authors.initials: K
authors.lastname: Offit
authors.forename: D F
authors.initials: DF
authors.lastname: Bajorin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics; D016190:Carboplatin / Q000627:therapeutic use*; D002945:Cisplatin / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D014644:Genetic Variation; D005838:Genotype; D018095:Germ-Line Mutation / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D016896:Treatment Outcome; D014571:Urologic Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D019459:Urothelium / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D016190:Carboplatin; D002945:Cisplatin
keywords: biomarkers; carboplatin; cisplatin; genetics; germline; urothelial