title: The role of SMAD4 in early-onset colorectal cancer.
abstract: OBJECTIVE
  Chromosomal loss within the region of 18q and loss of SMAD4 expression have been reported to be frequent somatic events during colorectal cancer tumour progression; however, their associations with age at onset have not been widely studied.
  
  
  METHODS
  We analysed 109 tumours from a population-based case-family study based on colorectal cancers diagnosed before the age of 45 years. These patients with early-onset colorectal cancer had been previously screened for germ-line mismatch repair gene mutations, microsatellite instability (that included the mononucleotide repeat in TGFbetaRII) and somatic k-ras mutations. We measured SMAD4 protein expression using immunohistochemistry and SMAD4 copy number using quantitative real-time PCR.
  
  
  RESULTS
  Loss of SMAD4 protein expression was observed in 27/109 (25%) of cancers tested and was more commonly observed in rectal tumours (15/41, 36%) when compared with tumours arising in the colon (11/66, 17%) (P = 0.04). There was no association between SMAD4 protein expression and TGFbetaR11 mutation status, SMAD4 copy number, family history, MSI status, tumour stage or grade.
  
  
  CONCLUSIONS
  Loss of SMAD4 expression is a common feature of early-onset colorectal tumours as it is in colorectal cancers diagnosed in other age-groups. Taken together, the molecular pathways (genetic and epigenetic) now known to be involved in early-onset colorectal cancer only explain a small proportion of the disease and require further exploration.
authors.affiliation: Department of Pathology, University of Melbourne, Victoria, Australia.
authors.forename: S G
authors.initials: SG
authors.lastname: Royce
authors.forename: K
authors.initials: K
authors.lastname: Alsop
authors.forename: A
authors.initials: A
authors.lastname: Haydon
authors.forename: L
authors.initials: L
authors.lastname: Mead
authors.forename: L D
authors.initials: LD
authors.lastname: Smith
authors.forename: A A
authors.initials: AA
authors.lastname: Tesoriero
authors.forename: G G
authors.initials: GG
authors.lastname: Giles
authors.forename: M A
authors.initials: MA
authors.lastname: Jenkins
authors.forename: J L
authors.initials: JL
authors.lastname: Hopper
authors.forename: M C
authors.initials: MC
authors.lastname: Southey
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism*; D056915:DNA Copy Number Variations; D005260:Female; D006801:Humans; D008297:Male; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
chemical_list: C497796:SMAD4 protein, human; D051901:Smad4 Protein