title: The role of functional polymorphisms in immune response genes as biomarkers of bacille Calmette-Guérin (BCG) immunotherapy outcome in bladder cancer: establishment of a predictive profile in a Southern Europe population.
abstract: OBJECTIVE
  To evaluate the predictive value of genetic polymorphisms in the context of bacille Calmette-Guérin (BCG) immunotherapy outcome and create a predictive profile that may allow discrimination of the risk of recurrence.
  
  
  METHODS
  In a dataset of 204 patients treated with BCG, we evaluated 42 genetic polymorphisms in 38 genes involved in the BCG mechanism of action, using Sequenom MassARRAY(®) technology. Stepwise multivariate Cox regression was used for data mining.
  
  
  RESULTS
  In agreement with previous studies we found that gender, age, tumour multiplicity and treatment scheme were associated with BCG failure. Using stepwise multivariate Cox regression analysis we propose the first predictive profile of BCG immunotherapy outcome and a risk score based on polymorphisms in immune system molecules [single nucleotide polymorphisms in tumour necrosis factor α (TNFA)-1031T/C (rs1799964), interleukin 2 receptor α (IL2RA) rs2104286 T/C, IL17A-197G/A (rs2275913), IL17RA-809A/G (rs4819554), IL18R1 rs3771171 T/C, intercellular adhesion molecule 1 (ICAM-1) K469E (rs5498), Fas ligand (FASL)-844T/C (rs763110) and TNF-related apoptosis-inducing ligand receptor 1 (TRAILR1)-397T/G (rs79037040)] in association with clinicopathological variables. This risk score allows the categorisation of patients into risk groups: patients within the low-risk group have a 90% chance of successful treatment, whereas patients in the high-risk group present a 75% chance of recurrence after BCG treatment.
  
  
  CONCLUSIONS
  We have established the first predictive score of BCG immunotherapy outcome combining clinicopathological characteristics and a panel of genetic polymorphisms. Further studies using an independent cohort are warranted. Moreover, the inclusion of other biomarkers may help to improve the proposed model.
authors.affiliation: Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, Porto, Portugal.|ICBAS, Abel Salazar Biomedical Sciences Institute, University of Porto, Porto, Portugal.|Nucleo de Investigação em Farmácia - Centro de Investigação em Saúde e Ambiente (CISA), School of Allied Health Sciences - Polytechnic Institute of Oporto, Porto, Portugal.|LPCC, Research Department-Portuguese League Against Cancer (NRNorte), Porto, Portugal.
authors.forename: Luís
authors.initials: L
authors.lastname: Lima
authors.affiliation: Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, Porto, Portugal.
authors.forename: Daniela
authors.initials: D
authors.lastname: Oliveira
authors.affiliation: Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, Porto, Portugal.|Mass Spectrometry Center of the University of Aveiro, Aveiro, Portugal.
authors.forename: José A
authors.initials: JA
authors.lastname: Ferreira
authors.affiliation: Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, Porto, Portugal.|Department of Pathology, Portuguese Institute of Oncology, Porto, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Tavares
authors.affiliation: Department of Urology, Portuguese Institute of Oncology, Porto, Portugal.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Cruz
authors.affiliation: LPCC, Research Department-Portuguese League Against Cancer (NRNorte), Porto, Portugal.|Molecular Oncology Group, Portuguese Institute of Oncology, Porto, Portugal.|Department of Pathology and Molecular Immunology, University of Porto, Porto, Portugal.|Health Faculty of University Fernando Pessoa, Porto, Portugal.
authors.forename: Rui
authors.initials: R
authors.lastname: Medeiros
authors.affiliation: Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, Porto, Portugal.|Health Faculty of University Fernando Pessoa, Porto, Portugal.|Department of Surgical Oncology, Portuguese Institute of Oncology, Porto, Portugal.
authors.forename: Lúcio
authors.initials: L
authors.lastname: Santos
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000283:Administration, Intravesical; D001500:BCG Vaccine / Q000008:administration & dosage*; D016022:Case-Control Studies; D005060:Europe / Q000453:epidemiology; D053222:Fas Ligand Protein / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D020381:Interleukin-17 / Q000235:genetics; D053727:Interleukin-18 Receptor alpha Subunit / Q000235:genetics; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics; D008297:Male; D009364:Neoplasm Recurrence, Local; D020641:Polymorphism, Single Nucleotide / Q000187:drug effects*; D053722:Receptors, Interleukin-17 / Q000235:genetics; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics; D012189:Retrospective Studies; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology*; D044465:White People / Q000235:genetics*
chemical_list: D000276:Adjuvants, Immunologic; D001500:BCG Vaccine; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C508717:IL17A protein, human; C109985:IL17RA protein, human; C508572:IL18R1 protein, human; C508017:IL2RA protein, human; D020381:Interleukin-17; D053727:Interleukin-18 Receptor alpha Subunit; D053645:Interleukin-2 Receptor alpha Subunit; D053722:Receptors, Interleukin-17; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1
keywords: BCG immunotherapy; bladder cancer; polymorphisms; predictive profile; risk score of recurrence