title: Inflammatory-Related Genetic Variants in Non-Muscle-Invasive Bladder Cancer Prognosis: A Multimarker Bayesian Assessment.
abstract: Increasing evidence points to the role of tumor immunologic environment on urothelial bladder cancer prognosis. This effect might be partly dependent on the host genetic context. We evaluated the association of SNPs in inflammation-related genes with non-muscle-invasive bladder cancer (NMIBC) risk-of-recurrence and risk-of-progression.
  
  
  
  We considered 822 NMIBC included in the SBC/EPICURO Study followed-up >10 years. We selected 1,679 SNPs belonging to 251 inflammatory genes. The association of SNPs with risk-of-recurrence and risk-of-progression was assessed using Cox regression single-marker (SMM) and multimarker methods (MMM) Bayes A and Bayesian LASSO. Discriminative abilities of the models were calculated using the c index and validated with bootstrap cross-validation procedures.
  
  
  
  While no SNP was found to be associated with risk-of-recurrence using SMM, three SNPs in TNIP1, CD5, and JAK3 showed very strong association with posterior probabilities >90% using MMM. Regarding risk-of-progression, one SNP in CD3G was significantly associated using SMM (HR, 2.69; P = 1.55 × 10(-5)) and two SNPs in MASP1 and AIRE, showed a posterior probability ≥80% with MMM. Validated discriminative abilities of the models without and with the SNPs were 58.4% versus 60.5% and 72.1% versus 72.8% for risk-of-recurrence and risk-of-progression, respectively.
  
  
  
  Using innovative analytic approaches, we demonstrated that SNPs in inflammatory-related genes were associated with NMIBC prognosis and that they improve the discriminative ability of prognostic clinical models for NMIBC.
  
  
  
  This study provides proof of concept for the joint effect of genetic variants in improving the discriminative ability of clinical prognostic models. The approach may be extended to other diseases. Cancer Epidemiol Biomarkers Prev; 25(7); 1144-50. ©2016 AACR.
authors.affiliation: Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. Urology Department, Henri Mondor Academic Hospital, Paris Est Créteil University, Créteil, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Masson-Lecomte
authors.affiliation: Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Evangelina
authors.initials: E
authors.lastname: López de Maturana
authors.affiliation: Biosciences Research Division, Department of Environment and Primary Industries, Agribio, Bundoora, Victoria, Australia. Department of Food and Agricultural Systems, University of Melbourne, Melbourne, Australia.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Goddard
authors.affiliation: Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Antoni
authors.initials: A
authors.lastname: Picornell
authors.affiliation: Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Rava
authors.affiliation: Human Genotyping-CEGEN Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: González-Neira
authors.affiliation: Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Mirari
authors.initials: M
authors.lastname: Márquez
authors.affiliation: Servicio de Oncología, Hospital Universitario Ramon y Cajal, Madrid, and Servicio de Oncología, Hospital Universitario de Elche, Elche, Spain.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Carrato
authors.affiliation: Department of Preventive Medicine, Universidad de Oviedo, Oviedo, Spain.
authors.forename: Adonina
authors.initials: A
authors.lastname: Tardon
authors.affiliation: Institut Municipal d'Investigació Mèdica - Hospital del Mar and Departament de Patologia, Hospital del Mar - IMAS, Barcelona, Spain.
authors.forename: Josep
authors.initials: J
authors.lastname: Lloreta
authors.affiliation: Division of Genetics and Epidemiology, Institute of Cancer Research, London, United Kingdom.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Garcia-Closas
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Department of Health and Human Services, Bethesda, Maryland.
authors.forename: Debra
authors.initials: D
authors.lastname: Silverman
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Department of Health and Human Services, Bethesda, Maryland.
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Rothman
authors.affiliation: Centre for Research in Environmental Epidemiology (CREAL) and Institut Municipal d'Investigació Mèdica - Hospital del Mar, Barcelona, Spain.
authors.forename: Manolis
authors.initials: M
authors.lastname: Kogevinas
authors.affiliation: Pathology Department, Henri Mondor Academic Hospital, Paris Est Créteil University, INSERM, Créteil, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Allory
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Department of Health and Human Services, Bethesda, Maryland.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chanock
authors.affiliation: Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Francisco X
authors.initials: FX
authors.lastname: Real
authors.affiliation: Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. nmalats@cnio.es.
authors.forename: Núria
authors.initials: N
authors.lastname: Malats
mesh_terms: D000368:Aged; D001499:Bayes Theorem; D014408:Biomarkers, Tumor / Q000235:genetics*; D002295:Carcinoma, Transitional Cell / Q000235:genetics* / Q000473:pathology; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D012307:Risk Factors; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor