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

Some studies have shown an inverse relationship between microsatellite inst ability 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 determin ed by a panel of 10 tetranucleotide repeats, the Bethesda consensus panel o f mono- and dinucleotide repeats, and coding mononucleotide repeats in tran sforming growth factor-beta receptor type II, bMSH3, BAX, hMSH6, and insuli n-like growth factor receptor type II. Mutations In codons 12 and 13 in K-r as were evaluated by sequencing. p53 overexpression Cas detected by immunoh istochemistry) 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 las 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 relation ships between microsatellite instability and ras gene mutations and p53 ove rexpression were shown to be Independent of tumor site In logistic regressi on analyses. All other measures of Instability also showed statistically si gnificant inverse relationships independent of tumor site with alterations In ras and p53, and instability results determined by the panel of 10 tetra nucleotide repeats were highly significantly related to those determined by the Bethesda consensus panel Coding mononucleotide repeat mutations were s ignificantly more com mon in unstable tumors than stable tumors (85.7% vers us 1.0%,P < 0.001), We conclude that there is an Inverse relationship betwe en microsatellite instability and mutations in p53 and K-ras, and that the molecular profile of colon cancers with microsatellite instability Is chara cterized by relatively infrequent mutations in Kras and p53 and relatively frequent mutations in coding mononucleotide repeats.