Biochemical and Biophysical Research Communications
Heterogeneity within and between primary colorectal carcinomas and matched metastases as revealed by analysis of Ki-ras and p53 mutations
Section snippets
Materials and methods
Patient’s features and tissue handling. Paired tumor and normal tissue samples were obtained from a consecutive series of 30 patients with colorectal carcinoma and colorectal liver metastasis.
Multiple samples were taken from different representative tumoral areas immediately after surgical resection. All tissues were carefully trimmed to remove as much non-neoplastic tissue as possible, avoiding any non-viable areas. Furthermore, samples of normal colon tissue (histologically free from tumor)
Results
The genetic status of the Ki-ras (exon 1) and p53 (exons 5–8) genes was compared in primary carcinomas and matched synchronous liver metastasis from 30 patients by SSCP and sequence analysis (see Materials and methods); in two cases, a metachronous metastasis specimen was also available and included in this study. Fig. 1 shows an example of electrophoretic pattern obtained upon SSCP analysis of the first exon of Ki-ras in two patients. It can be noticed that in some of these samples (as well as
Discussion
Our comparison of the genetic status of Ki-ras and p53 in primary colorectal carcinomas and matched liver metastases from 30 patients shows different pictures for the two genes.
In fact, although they were found to be mutated with the same frequency in primary tumors and in the metastatic tissues (14/30 vs 13/30 for Ki-ras and 13/30 versus 13/30 for p53), the same p53 mutation was detected in both tissues in 10/15 cases, while this happened only in 7/18 cases for Ki-ras. In particular in 77% of
Acknowledgment
This work was supported by grants from the MIUR (ex 60%).
References (21)
- et al.
The hallmarks of cancer
Cell
(2000) - et al.
Focus on colon cancer
Cancer Cell
(2002) - et al.
Know thy neighbor: stromal cells can contribute oncogenic signals
Curr. Opin. Genet. Dev.
(2001) - et al.
Cancer genes and the pathway they control
Nat. Med.
(2004) - et al.
Life (and death) in a malignant tumour
Nature
(1996) - et al.
Concordant p53 and DCC alterations and allelic losses on chromosomes 13q and 14q associated with liver metastases of colorectal carcinoma
Int. J. Cancer
(1993) - et al.
Increased incidence of p53 mutations is associated with hepatic metastasis in colorectal neoplastic progression
Oncogene
(1995) - et al.
Detection of DCC and Ki-ras gene alterations in colorectal carcinoma tissue as prognostic markers for liver metastatic recurrence
Cancer
(1996) - et al.
A phosphatase associated with metastasis of colorectal cancer
Science
(2001) - et al.
p53 gene mutations are not required for early dissemination of cancer cells
Proc. Natl. Acad. Sci. USA
(1999)
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