title: Promoter hypermethylation in tumour suppressor genes and response to interleukin-2 treatment in bladder cancer: a pilot study.
abstract: OBJECTIVE
  Non-muscle invasive bladder cancer (BC) is a highly recurrent disease, with the first recurrences arising shortly after transurethral resection of the bladder (TURB). Topical administration of interleukin-2 (IL-2) has been shown as an effective adjuvant therapy for BC; however, predictive biomarkers that may identify suitable subgroups of patients are lacking. In this pilot study we sought to determine the prognostic value of epigenetic and genetic inactivation of tumour suppressor genes (TSGs) among BC patients treated with IL-2.
  
  
  METHODS
  After complete TURB, patients with multifocal superficial BC were treated with five daily intravesical instillations of IL-2. Promoter hypermethylation in six TSGs and the TP53 gene mutations were prospectively assessed by methylation-specific PCR and automated capillary single-strand conformation polymorphism in 21 primary bladder cancer specimens and ten bladder wall biopsies collected during follow-up.
  
  
  RESULTS
  After IL-2 treatment, 9 out of 21 (43%) patients did not develop recurrent tumour within the 1 year of follow-up period. The mean duration of recurrence-free survival in the rest of the study group was 112 days. In the current pilot study, BC with p16 gene hypermethylation had a lower risk of recurrence after treatment with IL-2, as compared to IL-2 treated BC without p16 hypermethylation (p = 0.02). Significant associations were observed between tumour grade and the mean methylation index (p = 0.003), as well as the hypermethylation of the RARbeta gene (p = 0.048).
  
  
  CONCLUSIONS
  Our preliminary data suggest that DNA methylation biomarkers may assist in selection of BC patients for efficient IL-2 therapy.
authors.affiliation: Faculty of Natural Sciences, Vilnius University, Ciurlionio 21, 3101 Vilnius, Lithuania. sonata.jarmalaite@gf.vu.lt
authors.forename: Sonata
authors.initials: S
authors.lastname: Jarmalaite
authors.forename: Rasa
authors.initials: R
authors.lastname: Andrekute
authors.forename: Asta
authors.initials: A
authors.lastname: Scesnaite
authors.forename: Kestutis
authors.initials: K
authors.lastname: Suziedelis
authors.forename: Kirsti
authors.initials: K
authors.lastname: Husgafvel-Pursiainen
authors.forename: Feliksas
authors.initials: F
authors.lastname: Jankevicius
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D051017:Apoptosis Regulatory Proteins / Q000187:drug effects / Q000235:genetics; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000187:drug effects / Q000235:genetics; D003558:Cystoscopy; D019175:DNA Methylation / Q000187:drug effects*; D064550:Death-Associated Protein Kinases; D005260:Female; D016147:Genes, Tumor Suppressor / Q000187:drug effects; D019942:Genes, p16 / Q000187:drug effects; D016158:Genes, p53 / Q000187:drug effects; D006801:Humans; D007376:Interleukin-2 / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000187:drug effects; D010865:Pilot Projects; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011446:Prospective Studies; D018168:Receptors, Retinoic Acid / Q000187:drug effects / Q000235:genetics; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins / Q000187:drug effects / Q000235:genetics; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D007376:Interleukin-2; C411762:RASSF1 protein, human; D018168:Receptors, Retinoic Acid; D025521:Tumor Suppressor Proteins; C082925:retinoic acid receptor beta; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases