title: Genetic susceptibility to distinct bladder cancer subphenotypes.
abstract: BACKGROUND
  Clinical, pathologic, and molecular evidence indicate that bladder cancer is heterogeneous with pathologic/molecular features that define distinct subphenotypes with different prognoses. It is conceivable that specific patterns of genetic susceptibility are associated with particular subphenotypes.
  
  
  OBJECTIVE
  To examine evidence for the contribution of germline genetic variation to bladder cancer heterogeneity.
  
  
  METHODS
  The Spanish Bladder Cancer/EPICURO Study is a case-control study based in 18 hospitals located in five areas in Spain. Cases were patients with a newly diagnosed, histologically confirmed, urothelial cell carcinoma of the bladder from 1998 to 2001. Case diagnoses were reviewed and uniformly classified by pathologists following the World Health Organisation/International Society of Urological Pathology 1999 criteria. Controls were hospital-matched patients (n=1149).
  
  
  METHODS
  A total of 1526 candidate variants in 423 candidate genes were analysed. Three distinct subphenotypes were defined according to stage and grade: low-grade nonmuscle invasive (n=586), high-grade nonmuscle invasive (n=219), and muscle invasive (n=246). The association between each variant and subphenotype was assessed by polytomous risk models adjusting for potential confounders. Heterogeneity in genetic susceptibility among subphenotypes was also tested.
  
  
  CONCLUSIONS
  Two established bladder cancer susceptibility genotypes, NAT2 slow-acetylation and GSTM1-null, exhibited similar associations among the subphenotypes, as did VEGF-rs25648, which was previously identified in our study. Other variants conferred risks for specific tumour subphenotypes such as PMS2-rs6463524 and CD4-rs3213427 (respective heterogeneity p values of 0.006 and 0.004), which were associated with muscle-invasive tumours (per-allele odds ratios [95% confidence interval] of 0.56 [0.41-0.77] and 0.71 [0.57-0.88], respectively) but not with non-muscle-invasive tumours. Heterogeneity p values were not robust in multiple testing according to their false-discovery rate.
  
  
  CONCLUSIONS
  These exploratory analyses suggest that genetic susceptibility loci might be related to the molecular/pathologic diversity of bladder cancer. Validation through large-scale replication studies and the study of additional genes and single nucleotide polymorphisms are required.
authors.affiliation: Spanish National Cancer Research Centre, Madrid, Spain.
authors.forename: Lin T
authors.initials: LT
authors.lastname: Guey
authors.forename: Montserrat
authors.initials: M
authors.lastname: García-Closas
authors.forename: Cristiane
authors.initials: C
authors.lastname: Murta-Nascimento
authors.forename: Josep
authors.initials: J
authors.lastname: Lloreta
authors.forename: Laia
authors.initials: L
authors.lastname: Palencia
authors.forename: Manolis
authors.initials: M
authors.lastname: Kogevinas
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Rothman
authors.forename: Gemma
authors.initials: G
authors.lastname: Vellalta
authors.forename: M Luz
authors.initials: ML
authors.lastname: Calle
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Marenne
authors.forename: Adonina
authors.initials: A
authors.lastname: Tardón
authors.forename: Alfredo
authors.initials: A
authors.lastname: Carrato
authors.forename: Reina
authors.initials: R
authors.lastname: García-Closas
authors.forename: Consol
authors.initials: C
authors.lastname: Serra
authors.forename: Debra T
authors.initials: DT
authors.lastname: Silverman
authors.forename: Stephen
authors.initials: S
authors.lastname: Chanock
authors.forename: Francisco X
authors.initials: FX
authors.lastname: Real
authors.forename: Núria
authors.initials: N
authors.lastname: Malats
mesh_terms: D000368:Aged; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D001749:Urinary Bladder Neoplasms / Q000145:classification* / Q000235:genetics*
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