K-ras and p53 mutations in aberrant crypt foci and colonic tumors from colon cancer patients

• Published in: Cancer letters Vol. 115; no. 1; pp. 39 - 46
• Main Authors: Shivapurkar, N., Huang, L., Ruggeri, B., Swalsky, P.A., Bakker, A., Finkelstein, S., Frost, A., Silverberg, S.
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier Ireland Ltd 01-05-1997; Elsevier
• Subjects: Aberrant crypt foci; Adenoma - genetics; Biological and medical sciences; Carcinoma - genetics; Colon cancer; Colonic Neoplasms - genetics; Gastroenterology. Liver. Pancreas. Abdomen; Genes, p53; Genes, ras; Humans; K-ras; Medical sciences; Mutation; p53; Polymerase Chain Reaction; Polymorphism, Single-Stranded Conformational; Precancerous Conditions - genetics; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Tumors; Colon cancer; K-ras; Aberrant crypt foci; p53; Human; Premalignant lesion; Tumoral marker; Malignant tumor; In vitro; Colonic disease; TP53 Gene; Digestive diseases; Intestinal disease; Colon; Mutation; Detection; Onc gene; Comparative study; Tumor suppressor gene
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/S0304-3835(97)04709-5

Aberrant crypt foci (ACF) are microscopic lesions which can be detected, after methylene blue staining, in the overtly normal looking colonic mucosa of cancer patients. ACF have been postulated to be precursor lesions which develop into colorectal cancer. Mutations of
K-ras and
p53 are two important genetic events implicated in colon carcinogenesis. Mutations in
K-ras are detectable at earlier stages, while mutations in
p53 are detectable at later stages of colon carcinogenesis. Our objective was to compare the nature of genetic alterations in
K-ras (codon 12 and 13) and in
p53 (exon 4–9) between ACF and corresponding colonic tumors from cancer patients. ACF with ≥20 crypts/focus were harvested from overtly normal looking colonic mucosa of cancer patients at a distance of (approx.) 5 cm from the site of colonic tumors. The colonic tumors and ACF samples were compared for
K-ras codon 12 and 13 base pair sequence, using DNA sequencing and for
p53 (exon 5–9) allelic types, using PCR-SSCP and DNA sequencing. The results demonstrated a perfect correlation in terms of the type of
K-ras allele (wild or mutated) between the ACF (≥20 crypts/focus) and corresponding colonic tumors in
11
13
cancer patients. Analyses of
p53 mutations demonstrated the presence of
p53 mutations in colonic carcinomas from
10
13
patients. However,
p53 mutations could be detected in an ACF from only
1
13
patient. The results provides further evidence to the role of ACF as precursor to colon cancer. The presence of an identical
K-ras as well as
p53 mutation in an ACF and the corresponding colonic carcinoma in a patient suggests the possibility of existence of ACF that may be at a more advanced stage in the sequence of colonic tumorigenesis than others. In conclusion, the results suggest that a subset of ACF with higher multiplicity might be considered more likely to progress to more advanced lesions and should be explored as markers of colon cancer risk.