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. 1999 Jun;44(6):826–833. doi: 10.1136/gut.44.6.826

Genetic epidemiology of mutated K-ras proto-oncogene, altered suppressor genes, and microsatellite instability in colorectal adenomas

A Rashid 1, M Zahurak 1, S Goodman 1, S Hamilton 1
PMCID: PMC1727525  PMID: 10323885

Abstract

BACKGROUND—The genetic epidemiology of colorectal adenomas has not been studied prospectively in colonoscopy patients without cancer.
AIMS—To study genetic alterations in colorectal adenomas and correlate these with patient demographics and adenoma characteristics.
METHODS—Mutations and allelic deletions in 201 adenomas from 60 patients were compared with demographic features, adenoma characteristics, and family history.
RESULTS—The most common alteration was K-ras proto-oncogene mutation, present in 35% of adenomas and 65% of patients. Patients 65 years of age and older had a decreased probability of K-ras mutations (26% versus 45%). Overexpression of p53 gene product was present in only 6% of adenomas but was more frequent in villous or tubulovillous adenomas (19% versus 3%). Allelic loss of chromosome 18q was present in only 2% of adenomas and was significantly less frequent than p53 overexpression. DNA replication errors (RER) were present in 7% of adenomas and 15% of patients, including multiple adenomas in four patients (two with hereditary non-polyposis colorectal cancer syndrome). Only 36% of RER positive adenomas had alteration of BAT-26 alleles, none had alteration of BAT-25, and only one (8%) had mutation in the transforming growth factor β type II receptor gene. RER positive adenomas were more likely to have a K-ras mutation. In patients with multiple adenomas, there was concordance of p53 overexpression and RER but not of K-ras mutations. 
CONCLUSIONS—Genetic progression in colorectal adenomas is heterogeneous, involving factors related to patient age and the presence of RER for the occurrence of ras mutations, but different intraindividual characteristics for the occurrence of p53 alterations and RER.


Keywords: K-ras mutation; p53 gene; loss of 18q; microsatellite instability; replication error; TGFβRII

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Figure 1  .

Figure 1  

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Aspartic acid mutation of codon 12 of K-ras gene by ligation of allelic specific oligonucleotide. M, size marker; Ad, adenoma sample.

Figure 2  .

Figure 2  

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Immunohistochemistry for p53 gene products. (A) Focal staining of adenomatous epithelium. (B) Diffuse staining of an adenoma.

Figure 3  .

Figure 3  

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RER in colorectal adenomas. Instability in microsatellite markers is shown by additional bands (arrows). N, non-neoplastic; Ad, adenoma.

Figure 4  .

Figure 4  

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Adenoma (Ad 2) with shortening of BAT-26 allele (arrow). The normal length PCR product (Ad 1 and Ad 2) is indicated by an arrowhead.

Figure 5  .

Figure 5  

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Adenoma (Ad 2) with one bp deletion (arrow) in TGFβ type II receptor gene shown by PCR amplification of a 73 bp region. The normal length PCR product (Ad 1 and Ad 2) is indicated by an arrowhead.    

Figure 6  .

Figure 6  

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Genetic alterations in adenomas from female (A) and male (B) patients.

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