Heterogeneity within and between primary colorectal carcinomas and matched metastases as revealed by analysis of Ki-ras and p53 mutations

https://doi.org/10.1016/j.bbrc.2004.10.111Get rights and content

Abstract

Analysis of the genetic status of Ki-ras and p53 in primary colorectal carcinomas and matched colorectal liver metastasis from 30 patients reveals an overall heterogeneity both within and between the two tumoral tissues. Both genes were found mutated with a similar frequency in both tissues; however, identical mutations in primary tumor and matched metastasis were found less frequently in the case of the Ki-ras than the p53 gene. Only in three cases the same p53 and Ki-ras mutations found in the primary tumor were found also in the metastasis. In several metastatic specimens the DNA bearing a mutation detected also in the primary tumor appears significantly less abundant than the wild-type DNA. These data are discussed in the light of current models of primary tumor/metastasis relationships.

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)

  • D. Hanahan et al.

    The hallmarks of cancer

    Cell

    (2000)
  • S.D. Markowitz et al.

    Focus on colon cancer

    Cancer Cell

    (2002)
  • T.D. Tlsty et al.

    Know thy neighbor: stromal cells can contribute oncogenic signals

    Curr. Opin. Genet. Dev.

    (2001)
  • B. Vogelstein et al.

    Cancer genes and the pathway they control

    Nat. Med.

    (2004)
  • K.W. Kinzler et al.

    Life (and death) in a malignant tumour

    Nature

    (1996)
  • K. Ookawa 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)
  • W.V. Kastrinakis et al.

    Increased incidence of p53 mutations is associated with hepatic metastasis in colorectal neoplastic progression

    Oncogene

    (1995)
  • M. Kato et al.

    Detection of DCC and Ki-ras gene alterations in colorectal carcinoma tissue as prognostic markers for liver metastatic recurrence

    Cancer

    (1996)
  • S. Saha et al.

    A phosphatase associated with metastasis of colorectal cancer

    Science

    (2001)
  • S. Offner et al.

    p53 gene mutations are not required for early dissemination of cancer cells

    Proc. Natl. Acad. Sci. USA

    (1999)
There are more references available in the full text version of this article.

Cited by (88)

  • Biomarker concordance between primary colorectal cancer and its metastases

    2019, EBioMedicine
    Citation Excerpt :

    27 studies analysed biomarker concordance separately within these metastatic sites as displayed in Table 4, thus allowing comparison between metastatic location and the possible impact on concordance. Of these studies, 21 gave concordance data specific to liver metastases [44–46,49–51,53,56,61,63–65,69,70,72,77,80–82,94,100], 11 for lung metastases [38,42,49,59,60,65,68,84–87] and 12 for lymph nodes [46,47,49,52,57,60,61,67,68,75,84,87]. Only two studies provided separate concordance for peritoneal metastases and likewise only single studies for ovarian and bone metastases were available, with most studies grouping these with other metastatic sites [45,53,63,89].

  • ESMO consensus guidelines for the management of patients with metastatic colorectal cancer

    2016, Annals of Oncology
    Citation Excerpt :

    For example, patients whose mCRC is associated with RAS and BRAF mutations have worse clinical outcomes, with RAS mutations shown to be associated with an increased incidence of lung, bone and brain metastases [146]. Moreover there are data to suggest that tumour TS expression levels and RAS mutation status are altered by site of metastasis compared with the primary [23–36, 147]. For patients with colorectal liver metastases (CLM), the treatment strategy should be directed towards complete resection whenever possible, with both ‘oncological’ (prognostic) and ‘technical’ (surgical) criteria being considered when evaluating patients for surgery [148].

  • RAS mutations as predictive biomarkers in clinical management of metastatic colorectal cancer

    2016, Clinical Colorectal Cancer
    Citation Excerpt :

    This might be used as an alternative noninvasive source of tumor DNA for genotyping that could overcome many of the limitations associated with tumor tissue sampling, including intratumor heterogeneity and the feasibility of serial sampling.78-81 Occasional studies have reported the presence of independent KRAS mutations (eg, KRAS G12A and G13D) within the same tumor,69 between the primary and metastatic tumor,75 in different metastatic tumors,82 and within sera68 from the same patient. Such polyclonal mutations would indicate genuine biologic heterogeneity owing to the occurrence of later “branch” mutations and the emergence of different mutant subclones.

View all citing articles on Scopus
View full text