title: The detection of the methylated Wif-1 gene is more accurate than a fecal occult blood test for colorectal cancer screening.
abstract: BACKGROUND
  The clinical benefit of guaiac fecal occult blood tests (FOBT) is now well established for colorectal cancer screening. Growing evidence has demonstrated that epigenetic modifications and fecal microbiota changes, also known as dysbiosis, are associated with CRC pathogenesis and might be used as surrogate markers of CRC.
  
  
  METHODS
  We performed a cross-sectional study that included all consecutive subjects that were referred (from 2003 to 2007) for screening colonoscopies. Prior to colonoscopy, effluents (fresh stools, sera-S and urine-U) were harvested and FOBTs performed. Methylation levels were measured in stools, S and U for 3 genes (Wif1, ALX-4, and Vimentin) selected from a panel of 63 genes; Kras mutations and seven dominant and subdominant bacterial populations in stools were quantified. Calibration was assessed with the Hosmer-Lemeshow chi-square, and discrimination was determined by calculating the C-statistic (Area Under Curve) and Net Reclassification Improvement index.
  
  
  RESULTS
  There were 247 individuals (mean age 60.8±12.4 years, 52% of males) in the study group, and 90 (36%) of these individuals were patients with advanced polyps or invasive adenocarcinomas. A multivariate model adjusted for age and FOBT led to a C-statistic of 0.83 [0.77-0.88]. After supplementary sequential (one-by-one) adjustment, Wif-1 methylation (S or U) and fecal microbiota dysbiosis led to increases of the C-statistic to 0.90 [0.84-0.94] (p = 0.02) and 0.81 [0.74-0.86] (p = 0.49), respectively. When adjusted jointly for FOBT and Wif-1 methylation or fecal microbiota dysbiosis, the increase of the C-statistic was even more significant (0.91 and 0.85, p<0.001 and p = 0.10, respectively).
  
  
  CONCLUSIONS
  The detection of methylated Wif-1 in either S or U has a higher performance accuracy compared to guaiac FOBT for advanced colorectal neoplasia screening. Conversely, fecal microbiota dysbiosis detection was not more accurate. Blood and urine testing could be used in those individuals reluctant to undergo stool testing.
authors.affiliation: Department of Gastroenterology, APHP, Henri-Mondor hospital, Créteil, France; University of Paris Est Creteil, Créteil, France; Laboratoire d'Investigation Clinique EA 4393 EC2M3, Créteil, France.
authors.forename: Aurelien
authors.initials: A
authors.lastname: Amiot
authors.affiliation: Laboratoire d'Investigation Clinique EA 4393 EC2M3, Créteil, France; Bioscience Core Laboratories, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia.
authors.forename: Hicham
authors.initials: H
authors.lastname: Mansour
authors.affiliation: Department of Oncology, APHP, Henri-Mondor Hospital, Créteil, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Baumgaertner
authors.affiliation: Department of Gastroenterology, APHP, Henri-Mondor hospital, Créteil, France; University of Paris Est Creteil, Créteil, France.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Delchier
authors.affiliation: University of Paris Est Creteil, Créteil, France; Department of Oncology, APHP, Henri-Mondor Hospital, Créteil, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Tournigand
authors.affiliation: Commensals and Probiotics-Host Interactions Laboratory, INRA, MICALIS Institute, Jouy en Josas, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Furet
authors.affiliation: Laboratoire d'analyse, CPAM, Paris, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Carrau
authors.affiliation: University of Paris Est Creteil, Créteil, France; Laboratoire d'Investigation Clinique EA 4393 EC2M3, Créteil, France; Department of Public Health, APHP, Henri-Mondor Hospital, Créteil, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Canoui-Poitrine
authors.affiliation: Department of Gastroenterology, APHP, Henri-Mondor hospital, Créteil, France; University of Paris Est Creteil, Créteil, France; Laboratoire d'Investigation Clinique EA 4393 EC2M3, Créteil, France.
authors.forename: Iradj
authors.initials: I
authors.lastname: Sobhani
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000368:Aged; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000235:genetics; D019175:DNA Methylation; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009780:Occult Blood; D012097:Repressor Proteins / Q000235:genetics*; D012680:Sensitivity and Specificity
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D012097:Repressor Proteins; C485569:WIF1 protein, human