title: Genetic variation in the TP53 pathway and bladder cancer risk. a comprehensive analysis.
abstract: BACKGROUND
  Germline variants in TP63 have been consistently associated with several tumors, including bladder cancer, indicating the importance of TP53 pathway in cancer genetic susceptibility. However, variants in other related genes, including TP53 rs1042522 (Arg72Pro), still present controversial results. We carried out an in depth assessment of associations between common germline variants in the TP53 pathway and bladder cancer risk.
  
  
  METHODS
  We investigated 184 tagSNPs from 18 genes in 1,058 cases and 1,138 controls from the Spanish Bladder Cancer/EPICURO Study. Cases were newly-diagnosed bladder cancer patients during 1998-2001. Hospital controls were age-gender, and area matched to cases. SNPs were genotyped in blood DNA using Illumina Golden Gate and TaqMan assays. Cases were subphenotyped according to stage/grade and tumor p53 expression. We applied classical tests to assess individual SNP associations and the Least Absolute Shrinkage and Selection Operator (LASSO)-penalized logistic regression analysis to assess multiple SNPs simultaneously.
  
  
  RESULTS
  Based on classical analyses, SNPs in BAK1 (1), IGF1R (5), P53AIP1 (1), PMAIP1 (2), SERINPB5 (3), TP63 (3), and TP73 (1) showed significant associations at p-value≤0.05. However, no evidence of association, either with overall risk or with specific disease subtypes, was observed after correction for multiple testing (p-value≥0.8). LASSO selected the SNP rs6567355 in SERPINB5 with 83% of reproducibility. This SNP provided an OR = 1.21, 95%CI 1.05-1.38, p-value = 0.006, and a corrected p-value = 0.5 when controlling for over-estimation.
  
  
  CONCLUSIONS
  We found no strong evidence that common variants in the TP53 pathway are associated with bladder cancer susceptibility. Our study suggests that it is unlikely that TP53 Arg72Pro is implicated in the UCB in white Europeans. SERPINB5 and TP63 variation deserve further exploration in extended studies.
authors.affiliation: Spanish National Cancer Research Center (CNIO), Madrid, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Pineda
authors.affiliation: Spanish National Cancer Research Center (CNIO), Madrid, Spain.
authors.forename: Roger L
authors.initials: RL
authors.lastname: Milne
authors.affiliation: Systems Biology Department, University of Vic, Vic, Spain.
authors.forename: M Luz
authors.initials: ML
authors.lastname: Calle
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Department of Health and Human Services, Bethesda, Maryland, United States of America.
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Rothman
authors.affiliation: Spanish National Cancer Research Center (CNIO), Madrid, Spain.
authors.forename: Evangelina
authors.initials: E
authors.lastname: López de Maturana
authors.affiliation: Spanish National Cancer Research Center (CNIO), Madrid, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Herranz
authors.affiliation: Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain; Institut Municipal d'Investigació Mèdica - Hospital del Mar, Barcelona, Spain.
authors.forename: Manolis
authors.initials: M
authors.lastname: Kogevinas
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Department of Health and Human Services, Bethesda, Maryland, United States of America.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chanock
authors.affiliation: Department of Preventive Medicine, Universidad de Oviedo, Oviedo, Spain.
authors.forename: Adonina
authors.initials: A
authors.lastname: Tardón
authors.affiliation: Spanish National Cancer Research Center (CNIO), Madrid, Spain.
authors.forename: Mirari
authors.initials: M
authors.lastname: Márquez
authors.affiliation: Spanish National Cancer Research Center (CNIO), Madrid, Spain.
authors.forename: Lin T
authors.initials: LT
authors.lastname: Guey
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Department of Health and Human Services, Bethesda, Maryland, United States of America.
authors.forename: Montserrat
authors.initials: M
authors.lastname: García-Closas
authors.affiliation: Institut Municipal d'Investigació Mèdica - Hospital del Mar, Barcelona, Spain; Departament de Patologia, Hospital del Mar - IMAS, Barcelona, Spain.
authors.forename: Josep
authors.initials: J
authors.lastname: Lloreta
authors.affiliation: Spanish National Cancer Research Center (CNIO), Madrid, Spain.
authors.forename: Erin
authors.initials: E
authors.lastname: Baum
authors.affiliation: Spanish National Cancer Research Center (CNIO), Madrid, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: González-Neira
authors.affiliation: Servicio de Oncología, Hospital Universitario de Elche, Elche, Spain; Servicio de Oncología, Hospital Universitario Ramon y Cajal, Madrid, Spain.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Carrato
authors.affiliation: Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain; Institut de Biologia Evolutiva (UPF-CSIC), Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain; Instituto Nacional de Bioinformática, Barcelona, Spain.
authors.forename: Arcadi
authors.initials: A
authors.lastname: Navarro
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Department of Health and Human Services, Bethesda, Maryland, United States of America.
authors.forename: Debra T
authors.initials: DT
authors.lastname: Silverman
authors.affiliation: Spanish National Cancer Research Center (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: Spanish National Cancer Research Center (CNIO), Madrid, Spain.
authors.forename: Núria
authors.initials: N
authors.lastname: Malats
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D001749:Urinary Bladder Neoplasms / Q000235:genetics*; D055815:Young Adult
chemical_list: D016159:Tumor Suppressor Protein p53