Inverse Relationship between Microsatellite Instability and K- ras and p53 Gene Alterations in Colon Cancer

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 determi...

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Bibliographic Details
Published in:	The American journal of pathology Vol. 158; no. 4; pp. 1517 - 1524
Main Authors:	Samowitz, Wade S., Holden, Joseph A., Curtin, Karen, Edwards, Sandra L., Walker, Adrianne R., Lin, Heather A., Robertson, Margaret A., Nichols, Melanie F., Gruenthal, Kristin M., Lynch, Beverly J., Leppert, Mark F., Slattery, Martha L.
Format:	Journal Article
Language:	English
Published:	Bethesda, MD Elsevier Inc 01-04-2001 ASIP American Society for Investigative Pathology
Subjects:	Adult Aged Biological and medical sciences Codon - genetics Colonic Neoplasms - genetics Colonic Neoplasms - metabolism Gastroenterology. Liver. Pancreas. Abdomen Genes, p53 - genetics Genes, ras - genetics Humans Medical sciences Microsatellite Repeats - genetics Middle Aged Mutation Regular Stomach. Duodenum. Small intestine. Colon. Rectum. Anus Tumor Suppressor Protein p53 - metabolism Tumors Human Immunohistochemistry Carcinoma Malignant tumor Carcinogenesis Colonic disease Pathology TP53 Gene Microsatellite DNA C-Onc gene Digestive diseases Intestinal disease Instability Colon Mutation Molecular biology Protooncogene Tumor suppressor gene
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Summary:	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 mononucleotide repeats.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0002-9440 1525-2191
DOI:	10.1016/S0002-9440(10)64102-8