Kl. Woodford-richens et al., SMAD4 mutations in colorectal cancer probably occur before chromosomal instability, but after divergence of the microsatellite instability pathway, P NAS US, 98(17), 2001, pp. 9719-9723
Citations number
33
Categorie Soggetti
Multidisciplinary
Journal title
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Loss of chromosome 18q21 is well documented in colorectal cancer, and it ha
s been suggested that this loss targets the DCC, DPC4/SMAD4, and SMAD2 gene
s. Recently, the importance of SMAD4, a downstream regulator in the TGF-bet
a signaling pathway, in colorectal cancer has been highlighted, although th
e frequency of SMAD4 mutations appears much lower than that of 18q21 loss.
We set out to investigate allele loss, mutations, protein expression, and c
ytogenetics of chromosome 18 copy number in a collection of 44 colorectal c
ancer cell lines of known status with respect to microsatellite instability
(MSI). Fourteen of thirty-two MSI- lines showed loss of SMAD4 protein expr
ession; usually, one allele was lost and the other was mutated in one of a
number of ways, including deletions of various sizes, splice site changes,
and missense and nonsense point mutations (although no frameshifts). Of the
18 MSI- cancers with retained SMAD4 expression, four harbored missense mut
ations in the 3' part of the gene and showed allele loss. The remaining 14
MSI- lines had no detectable SMAD4 mutation, but all showed allele loss at
SMAD4 and/or DCC. SMAD4 mutations can therefore account for about 50-60% of
the 18q21 allele loss in colorectal cancer. No MSI+ cancer showed loss of
SMAD4 protein or SMAD4 mutation, and very few had allelic loss at SMAD4 or
DCC, although many of these MSI+ lines did carry TGFBIIR changes. Although
SMAD4 mutations have been associated with late-stage or metastatic disease,
our combined molecular and cytogenetic data best fit a model in which SMAD
4 mutations occur before colorectal cancers become aneuploid/polyploid, but
after the MSI+ and MSI- pathways diverge. Thus, MSI+ cancers may diverge f
irst, followed by CIN+ (chromosomal instability) cancers, leaving other can
cers to follow a CIN-MSI- pathway.