Predictive value of nuclear beta-catenin expression for the occurrence of distant metastases in rectal cancer.
OBJECTIVE
Adenomatous polyposis coli protein, glycogen synthetase kinase-3-beta, T cell transcription factor/lymphoid enhancer-binding factor, and beta-catenin modulate cell differentiation and proliferation via the expression of effector genes. It has recently been postulated that beta-catenin is a potent oncogene of sporadic colorectal carcinogenesis and a prognostic tumor marker. Our aim was to investigate whether the nuclear overexpression of beta-catenin, possibly caused by mutations in exon 3 of beta-catenin (CTNNB1), is correlated with distant metastatic spread or disease-free survival in rectal carcinoma.


METHODS
Immunohistochemical analysis was performed with an anti-beta-catenin-monoclonal antibody on paraffin sections of two groups of patients (n = 2 x 77) with rectal carcinoma curatively treated by surgery alone. The patients selected were all free of local disease, to exclude surgical influence. Patient groups were matched for age, gender, International Union Against Cancer stage, and year of operation (1982 to 1991) and differed only in subsequent metachronous distant metastatic spread. Follow-up was prospective (median, 9.6 years). Three staining patterns were defined: membranous (normal), diffuse cytoplasmic (pathologic), and intense nuclear staining (pathologic). When intense nuclear staining was defined, the specimen was microdissected. Then, DNA was isolated, polymerase chain reaction-amplified, and sequenced to detect mutations in exon 3.


RESULTS
Nuclear overexpression of beta-catenin correlated neither with distant metastatic spread (chi-squared, 0.37; P = 0.79) nor with disease-free survival (log-rank with trend, P = 0.62). No mutations were found in the area of the serine/threonine-kinase glycogen synthetase kinase-3-beta-phosphorylation site in exon 3 (CTNNB1) of beta-catenin.


CONCLUSIONS
Although beta-catenin seems to play an important role in early colorectal carcinogenesis, its value as a prognostic marker is questionable. It must be assumed that metastatic ability is determined by other factors than the disturbance of the beta-catenin T cell transcription factor/lymphoid enhancer-binding factor cascade and that other mechanisms might cause the observed nuclear translocation of beta-catenin.
Günther
K
K
Department of Surgery, University of Erlangen, Germany.
Brabletz
T
T
Kraus
C
C
Dworak
O
O
Reymond
M A
MA
Jung
A
A
Hohenberger
W
W
Kirchner
T
T
Köckerling
F
F
Ballhausen
W G
WG
D000230:Adenocarcinoma / Q000378:metabolism* / Q000401:mortality / Q000556:secondary* / Q000601:surgery; D014408:Biomarkers, Tumor; D015820:Cadherins / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000378:metabolism*; D018572:Disease-Free Survival; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000378:metabolism*; D011237:Predictive Value of Tests; D011379:Prognosis; D012004:Rectal Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology* / Q000601:surgery; D017422:Sequence Analysis, DNA; D015534:Trans-Activators; D051176:beta Catenin
D014408:Biomarkers, Tumor; C495270:CTNNB1 protein, human; D015820:Cadherins; D003598:Cytoskeletal Proteins; D004273:DNA, Neoplasm; D009687:Nuclear Proteins; D015534:Trans-Activators; D051176:beta Catenin