title: Molecular heterogeneity and prognostic implications of synchronous advanced colorectal neoplasia.
abstract: BACKGROUND
  It is uncertain whether synchronous colorectal cancers (S-CRCs) preferentially develop through widespread DNA methylation and whether they have a prognosis worse than solitary CRC. As tumours with microsatellite instability (MSI) may confound the effect of S-CRC methylation on outcome, we addressed this issue in a series of CRC characterised by BRAF and MS status.
  
  
  METHODS
  Demographics, clinicopathological records and disease-specific survival (DSS) were assessed in 881 consecutively resected CRC undergoing complete colonoscopy. All tumours were typed for BRAF(c.1799T>A) mutation and MS status, followed by search of germ-line mutation in patients with MSI CRC.
  
  
  RESULTS
  Synchronous colorectal cancers (50/881, 5.7%) were associated with stage IV microsatellite-stable (MSS) CRC (19/205, 9.3%, P=0.001) and with HNPCC (9/32, 28%, P<0.001). BRAF mutation (60/881, 6.8%) was associated with sporadic MSI CRC (37/62, 60%, P<0.001) but not with S-CRC (3/50, 6.0%, P=0.96). Synchronous colorectal cancer (HR 1.82; 95% CI 1.15-2.87; P=0.01), synchronous advanced adenoma (HR 1.81; 95% CI 1.27-2.58; P=0.001), and BRAF(c.1799T>A) mutation (HR 2.16; 95% CI 1.25-3.73; P=0.01) were stage-independent predictors of death from MSS CRC. Disease-specific survival of MSI CRC patients was not affected by S-CRC (HR 0.74; 95% CI 0.09-5.75; P=0.77).
  
  
  CONCLUSIONS
  Microsatellite-stable CRCs have a worse prognosis if S-CRC or synchronous advanced adenoma are diagnosed. The occurrence and the enhanced aggressiveness of synchronous MSS advanced neoplasia are not associated with BRAF mutation.
authors.affiliation: 1] Department of Gastroenterology, Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano, Milan, Italy [2] Department of Biotechnology and Translational Medicine, Via Vanvitelli 32, 20133 Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Malesci
authors.affiliation: 1] Laboratory of Molecular Gastroenterology, Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano, Milan, Italy [2] Ph.D. Program in Molecular Medicine at the University of Milan, Via F.lli Cervi 93, 20090 Segrate, Milan, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Basso
authors.affiliation: Laboratory of Molecular Gastroenterology, Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano, Milan, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Bianchi
authors.affiliation: Department of Gastroenterology, Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano, Milan, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Fini
authors.affiliation: Laboratory of Molecular Gastroenterology, Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano, Milan, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Grizzi
authors.affiliation: Laboratory of Molecular Gastroenterology, Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano, Milan, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Celesti
authors.affiliation: Laboratory of Molecular Gastroenterology, Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano, Milan, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Di Caro
authors.affiliation: Department of Gastroenterology, Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano, Milan, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Delconte
authors.affiliation: Department of Gastroenterology, Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano, Milan, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Dattola
authors.affiliation: Department of Gastroenterology, Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano, Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Repici
authors.affiliation: 1] Department of Biotechnology and Translational Medicine, Via Vanvitelli 32, 20133 Milan, Italy [2] Department of Pathology, Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Roncalli
authors.affiliation: 1] Department of Biotechnology and Translational Medicine, Via Vanvitelli 32, 20133 Milan, Italy [2] Department of Surgery at the Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Montorsi
authors.affiliation: 1] Department of Gastroenterology, Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano, Milan, Italy [2] Laboratory of Molecular Gastroenterology, Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano, Milan, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Laghi
mesh_terms: D000236:Adenoma / Q000235:genetics; D000368:Aged; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D018895:Microsatellite Repeats; D008875:Middle Aged; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics
chemical_list: C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf