Annals of Oncology 13:1438-1446, 2002
© 2002 European Society for Medical Oncology
Original Paper |
Specific codon 13 K-ras mutations are predictive of clinical outcome in colorectal cancer patients, whereas codon 12 K-ras mutations are associated with mucinous histotype
Department of Oncology, 1 Section of Molecular Oncology, 5 Section of Medical Oncology and 2 Section of Oncology Surgery, Regional Reference Center for the Biomolecular Characterization of Neoplasies and Genetic Screening of Hereditary Tumors, Palermo; 6 Institute of Pathology, School of Medicine; 3 Department of Cellular and Development Biology, Biomolecular Section, University of Palermo, Palermo; 4 Epidemiological Observatory, Center of Sicilian Region, Palermo; 7 Medical Oncology Unit, Ospedali Riuniti Bergamo, Italy
Received 9 November 2001; revised 12 February 2002; accepted 11 March 2002
Background:
K-ras mutations, one of the earliest events observed in colorectal carcinogenesis, are mostly found in codons 12 and 13, and less frequently in codon 61, all three of which are estimated to be critical for the biological activity of the protein. Nevertheless the prognostic significance of such mutations remains controversial. Our purpose was to assess whether any or specific K-ras mutations in primary colorectal cancer had prognostic significance and were linked to clinico-pathological parameters.
Patients and methods:
Paired tumor and normal tissue samples from a consecutive series of 160 untreated patients (median of follow up 71 months), undergoing resective surgery for primary colorectal carcinoma, were prospectively studied for K-ras mutations by PCR/single strand conformation polymorphism sequencing.
Results:
Seventy-four of the 160 (46%) primary colorectal carcinomas presented mutations in K-ras: 54% in codon 12, 42% in codon 13 (particularly G
A transition) and 4% in both. Codon 12 K-ras mutations were associated with mucinous histotype (P <0.01), while codon 13 K-ras mutations were associated with advanced Dukes’ stage (P <0.05), lymph-node metastasis (P <0.05) and high S-phase fraction (P <0.05). Multivariate analysis showed that codon 13 K-ras mutations, but not any mutation, were independently related to risk of relapse or death.
Conclusions:
Our results suggest that codon 12 K-ras mutations may have a role in the mucinous differentiation pathway, while codon 13 mutations have biological relevance in terms of colorectal cancer clinical outcome.
Key words: colorectal carcinoma, DNA ploidy, K-ras mutations, prognosis
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