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K-ras oncogene mutations in sporadic colorectal cancer in The Netherlands Cohort Study

K-ras oncogene mutations in sporadic colorectal cancer in The Netherlands Cohort Study Activation of K-ras oncogene has been implicated in colorectal carcinogenesis, being mutated in 30–60% of the adenocarcinomas. In this study, 737 incident colorectal cancer (CRC) patients, originating from 120 852 men and women (55–69 years at baseline) participating in the Netherlands Cohort Study (NLCS), were studied in order to evaluate subgroups with respect to K-ras mutation status. Mutation analysis of the exon 1 fragment of the K-ras oncogene, spanning codons 8–29, was performed on archival colorectal adenocarcinoma samples of all patients using macrodissection, nested PCR and direct sequencing of purified fragments. The method of mutation detection was validated by the confirmation of reported K-ras status in CRC cell lines, a good correlation between fresh-frozen and routinely fixed, paraffin-embedded tissue, a detection limit of 5% mutated DNA and a good reproducibility. Various types of K-ras mutations were evaluated with respect to tumour sub-localization, Dukes' stage and tumour differentiation. In 37% (271/737) of the patients, the exon 1 fragment of K-ras gene was found to be mutated. The predominant mutations are G>A transitions and G>T transversions, and codons 12 and 13 are the most frequently affected codons. Patients with a rectal tumour were found to have the highest frequency of G>T transversions as compared with patients with a colon or rectosigmoid tumour. This difference appeared to be confined to women with a rectal tumour harbouring G>T transversions. No significant differences were observed for Dukes' stage with respect to types of K-ras mutation, which does not support direct involvement of the K-ras oncogene in adenocarcinoma progression. The equal distribution of K-ras mutations among cases with or without a family history of colorectal cancer argues against an important role for this mutation in familial colorectal cancer, and could imply that K-ras mutations are more probably involved in environmental mechanisms of colorectal carcinogenesis. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Carcinogenesis Oxford University Press

K-ras oncogene mutations in sporadic colorectal cancer in The Netherlands Cohort Study

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References (55)

Publisher
Oxford University Press
Copyright
© Oxford University Press. All rights reserved
ISSN
0143-3334
eISSN
1460-2180
DOI
10.1093/carcin/bgg009
Publisher site
See Article on Publisher Site

Abstract

Activation of K-ras oncogene has been implicated in colorectal carcinogenesis, being mutated in 30–60% of the adenocarcinomas. In this study, 737 incident colorectal cancer (CRC) patients, originating from 120 852 men and women (55–69 years at baseline) participating in the Netherlands Cohort Study (NLCS), were studied in order to evaluate subgroups with respect to K-ras mutation status. Mutation analysis of the exon 1 fragment of the K-ras oncogene, spanning codons 8–29, was performed on archival colorectal adenocarcinoma samples of all patients using macrodissection, nested PCR and direct sequencing of purified fragments. The method of mutation detection was validated by the confirmation of reported K-ras status in CRC cell lines, a good correlation between fresh-frozen and routinely fixed, paraffin-embedded tissue, a detection limit of 5% mutated DNA and a good reproducibility. Various types of K-ras mutations were evaluated with respect to tumour sub-localization, Dukes' stage and tumour differentiation. In 37% (271/737) of the patients, the exon 1 fragment of K-ras gene was found to be mutated. The predominant mutations are G>A transitions and G>T transversions, and codons 12 and 13 are the most frequently affected codons. Patients with a rectal tumour were found to have the highest frequency of G>T transversions as compared with patients with a colon or rectosigmoid tumour. This difference appeared to be confined to women with a rectal tumour harbouring G>T transversions. No significant differences were observed for Dukes' stage with respect to types of K-ras mutation, which does not support direct involvement of the K-ras oncogene in adenocarcinoma progression. The equal distribution of K-ras mutations among cases with or without a family history of colorectal cancer argues against an important role for this mutation in familial colorectal cancer, and could imply that K-ras mutations are more probably involved in environmental mechanisms of colorectal carcinogenesis.

Journal

Carcinogenesis – Oxford University Press

Published: Apr 1, 2003

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