Wnt signalling in adenomas of familial adenomatous polyposis patients.
BACKGROUND
Epigenetic silencing of Wnt antagonists and expression changes in genes associated with Wnt response pathways occur in early sporadic colorectal tumourigenesis, indicating that tumour cells are more sensitive to Wnt growth factors and respond differently. In this study, we have investigated whether similar changes occur in key markers of the Wnt response pathways in the genetic form of the disease, familial adenomatous polyposis (FAP).


METHODS
We investigated epigenetic and expression changes using pyrosequencing and real-time RT-PCR in samples from seven patients without neoplasia, and matched normal and tumour tissues from 22 sporadic adenoma and 14 FAP patients.


RESULTS
We found that 17 out of 24 (71%) FAP adenomas were hypermethylated at sFRP1, compared with 20 out of 22 (91%) of sporadic cases. This was reflected at the level of sFRP1 transcription, where 73% of FAP and 100% of sporadic cases were down-regulated. Increased expression levels of c-myc and FZD3 were less common in FAP (35 and 46% respectively) than sporadic tumours (78 and 67% respectively).


CONCLUSIONS
Overall, the changes in expression and methylation were comparable, although the degree of change was generally lower in the FAP adenomas. Molecular heterogeneity between multiple adenomas from individual FAP patients may reflect different developmental fates for these premalignant tumours.
Caldwell
G M
GM
School of Cancer Sciences, The University of Birmingham, Edgbaston, Birmingham, B15 2TH, UK. G.M.Caldwell@bham.ac.uk
Jones
C E
CE
Ashley
A M
AM
Wei
W
W
Hejmadi
R K
RK
Morton
D G
DG
Matthews
G M
GM
D011125:Adenomatous Polyposis Coli / Q000378:metabolism*; D000328:Adult; D000368:Aged; D001483:Base Sequence; D019175:DNA Methylation; D017931:DNA Primers; D044127:Epigenesis, Genetic; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*
D017931:DNA Primers; D051153:Wnt Proteins