Mutations in the APC tumour suppressor gene cause chromosomal instability

Two forms of genetic instability have been described in colorectal cancer(1 ): microsatellite instability and chromosomal instability. Microsatellite i nstability results from mutations in mismatch repair genes; chromosomal ins tability is the hallmark of many colorectal cancers, although it is not com pletely understood at the molecular level. As truncations of the Adenomatou s Polyposis Coli (APC) gene are found in most colorectal tumours, we though t that mutations in APC might be responsible for chromosomal instability. T o test this hypothesis, we examined mouse embryonic stem (ES) cells homozyg ous for Min (multiple intestinal neoplasia) or Apc1638T alleles, Here we sh ow that Ape mutant ES cells display extensive chromosome and spindle aberra tions, providing genetic evidence for a role of APC in chromosome segregati on. Consistent with this, APC accumulates at the kinetochore during mitosis , Ape mutant cells form mitotic spindles with an abundance of microtubules that inefficiently connect with kinetochores. This phenotype is recapitulat ed by the induced expression of a 253-amino-acid carboxy-terminal fragment of APC in microsatellite unstable colorectal cancer cells, We conclude that loss of APC sequences that lie C-terminal to the beta -catenin regulatory domain contributes to chromosomal instability in colorectal cancer.