The role of SMAD4 in early-onset colorectal cancer.
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.
Royce
S G
SG
Department of Pathology, University of Melbourne, Victoria, Australia.
Alsop
K
K
Haydon
A
A
Mead
L
L
Smith
L D
LD
Tesoriero
A A
AA
Giles
G G
GG
Jenkins
M A
MA
Hopper
J L
JL
Southey
M C
MC
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
C497796:SMAD4 protein, human; D051901:Smad4 Protein