[beta-Catenine as a genomic target of high-grade microsatellite instability in colorectal cancer].
OBJECTIVE
Various inherited and acquired alterations affecting the genes and gene products of the WNT pathway appear to be involved in the different molecular routes leading to colorectal cancer (CRC). This study was initiated to investigate the prevalence of somatic mutations in the beta-catenin gene (CTNNB1) and the associated pathology in CRC with defective DNA mismatch repair.


METHODS
Paraffin and/or frozen sections of 33 primary CRC (including any liver and lymph node metastases present) with high-grade microsatellite instability (MSI-H; i.e. with > or = 5 unstable microsatellite markers of 10 tested) were polytopically fractionated by microdissection. Genomic and c-DNA samples were sequenced across exons 2-4 of CTNNB1 and the expression patterns of beta-catenin (beta-C) analyzed by immunohistology and Western blotting.


RESULTS
Seven somatic mutations affecting phosphorylation sites of exon 3 (2 deletions also encompassing parts of either intron 2 or exon 4 [delta X2/3 bzw. delta X3/4] and 5 missense mutations [2 x T41A, 2 x S45F, S45P]) were identified. Two mutations (delta X3/4 and S45F) were concordantly present in CRC primaries and their respective metastases whereas the S45P mutation was restricted to a hepatic metastasis. In the delta X2/3 CRC primary only a shortened 66 kD CTNNB1 gene product was present while its associated liver metastasis showed a total loss of beta-C expression.


CONCLUSIONS
Both exon 3 and the entire locus coding for beta-C are somatically altered in approximately 20% of CRC with MSI-H at different stages of tumor progression. Thus CTNNB1 appears to be a genomic target for complex oncogenic mutations and deletional processes in a substantial fraction of this molecular subset of CRC.
Kölble
K
K
Institut für Pathologie, Universitätsklinikum Charité, Humboldt-Universität, Berlin.
Barthel
B
B
Ullrich
O
O
Pidde
H
H
Döhring
C
C
Rüschoff
J
J
Schlag
P M
PM
Dietel
M
M
D015820:Cadherins / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D003598:Cytoskeletal Proteins / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics; D005091:Exons; D017491:Genes, APC; D005819:Genetic Markers; D006801:Humans; D018895:Microsatellite Repeats / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D012189:Retrospective Studies; D015534:Trans-Activators; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin
C495270:CTNNB1 protein, human; D015820:Cadherins; D003598:Cytoskeletal Proteins; D004273:DNA, Neoplasm; D005819:Genetic Markers; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin
beta-Catenin als genomischer Zielort der hochgradigen Mikrosatelliteninstabilität in kolorektalen Karzinomen.