Am J Pathol  2001 Apr;158(4):1517-24 

Inverse relationship between microsatellite instability and K-ras and p53 gene
alterations in colon cancer.

Samowitz WS, Holden JA, Curtin K, Edwards SL, Walker AR, Lin HA, Robertson MA,
Nichols MF, Gruenthal KM, Lynch BJ, Leppert MF, Slattery ML.

Department of Pathology, University of Utah Health Sciences Center, 50 North
Medical Dr., Salt Lake City, UT 84132, USA. wsamowitz@msscc.med.utah.edu

Some studies have shown an inverse relationship between microsatellite
instability in colon cancer and mutations in p53 and K-ras, whereas others have
not. We therefore evaluated these features in a population-based sample of 496
individuals with colon cancer. Microsatellite instability was determined by a
panel of 10 tetranucleotide repeats, the Bethesda consensus panel of mono- and
dinucleotide repeats, and coding mononucleotide repeats in transforming growth
factor-beta receptor type II, hMSH3, BAX, hMSH6, and insulin-like growth factor
receptor type II. Mutations in codons 12 and 13 in K-ras were evaluated by
sequencing. p53 overexpression (as detected by immunohistochemistry) was used as
an indicator of p53 mutation; this was evaluated in 275 of the tumors. K-ras
mutations were present in 33.2% of tumors, p53 overexpression in 51.5%, and
microsatellite instability (as determined by the Bethesda consensus panel) in
12.5%. K-ras mutations were significantly less common in unstable tumors than
stable tumors (11.8% versus 36.9%, P: < 0.001). p53 overexpression was
significantly less common in unstable tumors than stable tumors (20.0% versus
55.7%, P: < 0.001). These inverse relationships between microsatellite
instability and ras gene mutations and p53 overexpression were shown to be
independent of tumor site in logistic regression analyses. All other measures of
instability also showed statistically significant inverse relationships
independent of tumor site with alterations in ras and p53, and instability
results determined by the panel of 10 tetranucleotide repeats were highly
significantly related to those determined by the Bethesda consensus panel.
Coding mononucleotide repeat mutations were significantly more common in
unstable tumors than stable tumors (85.7% versus 1.0%, P: < 0.001). We conclude
that there is an inverse relationship between microsatellite instability and
mutations in p53 and K-ras, and that the molecular profile of colon cancers with
microsatellite instability is characterized by relatively infrequent mutations
in K-ras and p53 and relatively frequent mutations in coding