This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zhu, D. Articles by Whiteside, T. L. Search for Related Content PubMed PubMed Citation Articles by Zhu, D. Articles by Whiteside, T. L.

K-ras Gene Mutations in Normal Colorectal Tissues from K-ras Mutation-positive Colorectal Cancer Patients¹

Department of Environmental and Occupational Health [D. Z., P. K.], Pathology [S. D. F., P. S., A. B., T. L. W.]. and Epidemiology [J. W.], and University of Pittsburgh Cancer Institute [P. K., J. W., T. L. W.], University of Pittsburgh, Pittsburgh, Pennsylvania 15238; and NIH. Bethesda, Maryland 20892 [S. S.]

K-ras gene mutations have been reported as early events in colorectal tumorigenesis, but their role in tumor initiation and development is still unclear. To analyze and compare K-ras mutational patterns between colorectal tissues at different stages of tumor progression in individual patients, 65 colorectal tissue samples, including carcinoma, adenoma, histologically normal mucosa, submucosal muscularis propria, and histologically normal mucosa distant from tumor, were obtained from 13 patients with colorectal cancer. In addition, normal mucosal tissues obtained from four normal individuals were analyzed. Each of the 13 tumors was shown previously to harbor a mutation in either codon 12 or 13 of the K-ras gene by direct sequencing. These tissues were reanalyzed, using the recently established mutant allele enrichment + denaturing gradient gel electrophoresis method, which can detect one mutant allele in 10⁴–10⁵ normal alleles, thus allowing for the analysis of infrequent cells bearing mutations against the background of wild-type cells. No K-ras codon 12 mutation was detected by this method in the histologically normal mucosal tissues sampled at the margin of resection distant from the tumor or in those obtained from four normal individuals. On the other hand, these mutations were detected in 9 of 10 adenoma and 6 of 10 mucosa samples from 10 patients with known K-ras codon 12 mutations, and also in 2 of 3 carcinoma, 2 of 3 adenoma, and 1 of 3 mucosa samples obtained from 3 patients with known K-ras codon 13 mutations. Thus, K-ras codon 12 mutations were found to occur with a high frequency (53.8%) in histologically normal mucosa adjacent to tumors of patients with K-ras mutation-positive colorectal cancer, suggesting that they may be useful biomarkers for early detection of colorectal cancer. Furthermore, multiple K-ras mutations were found in tissues of nearly half of the 13 patients, indicating that distinct evolutionary subclones may be involved in the development of tumor in some patients with colorectal cancer.

¹ Supported by NIH Contract CN-15393-02 (Early Detection Research Network) and American Cancer Society Institutional Research Grant IRG-58-32.

² To whom requests for reprints should be addressed, at Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, 260 Kappa Drive, Pittsburgh, PA 15238. Phone: (412) 967-6526; Fax: (412) 624-1020.

Received 6/24/96. Accepted 4/15/97.

This article has been cited by other articles:

				J. G. Einspahr, M. E. Martinez, R. Jiang, C.-H. Hsu, A. K. Bhattacharrya, D. J. Ahnen, E. T. Jacobs, P. S. Houlihan, C. R. Webb, D. S. Alberts, et al. Associations of Ki-ras Proto-oncogene Mutation and p53 Gene Overexpression in Sporadic Colorectal Adenomas with Demographic and Clinicopathologic Characteristics. Cancer Epidemiol. Biomarkers Prev., August 1, 2006; 15(8): 1443 - 1450. [Abstract] [Full Text] [PDF]

				C. Greco, R. Vona, M. Cosimelli, P. Matarrese, E. Straface, P. Scordati, D. Giannarelli, V. Casale, D. Assisi, M. Mottolese, et al. Cell surface overexpression of galectin-3 and the presence of its ligand 90k in the blood plasma as determinants in colon neoplastic lesions Glycobiology, September 1, 2004; 14(9): 783 - 792. [Abstract] [Full Text] [PDF]

				B M Ryan, F Lefort, R McManus, J Daly, P W N Keeling, D G Weir, and D Kelleher A prospective study of circulating mutant KRAS2 in the serum of patients with colorectal neoplasia: strong prognostic indicator in postoperative follow up Mol. Pathol., June 1, 2003; 56(3): 172 - 179. [Abstract] [Full Text] [PDF]

				B M Ryan, F Lefort, R McManus, J Daly, P W N Keeling, D G Weir, and D Kelleher A prospective study of circulating mutant KRAS2 in the serum of patients with colorectal neoplasia: strong prognostic indicator in postoperative follow up Gut, January 1, 2003; 52(1): 101 - 108. [Abstract] [Full Text] [PDF]

				E. Lopez-Crapez, T. Livache, J. Marchand, and J. Grenier K-ras Mutation Detection by Hybridization to a Polypyrrole DNA Chip Clin. Chem., February 1, 2001; 47(2): 186 - 194. [Abstract] [Full Text] [PDF]

				M. S. Kopreski, F. A. Benko, D. J. Borys, A. Khan, T. J. McGarrity, and C. D. Gocke Somatic Mutation Screening: Identification of Individuals Harboring K-ras Mutations With the Use of Plasma DNA J Natl Cancer Inst, June 7, 2000; 92(11): 918 - 923. [Abstract] [Full Text] [PDF]

				C. C. Schimanski, U. Linnemann, and M. R. Berger Sensitive Detection of K-ras Mutations Augments Diagnosis of Colorectal Cancer Metastases in the Liver Cancer Res., October 1, 1999; 59(20): 5169 - 5175. [Abstract] [Full Text] [PDF]

				S.-J. C. Wei, R. L. Chang, K. A. Merkler, M. Gwynne, X. X. Cui, B. Murthy, M.-T. Huang, J.-G. Xie, Y.-P. Lu, Y.-R. Lou, et al. Dose-dependent mutation profile in the c-Ha-ras proto-oncogene of skin tumors in mice initiated with benzo[a]pyrene Carcinogenesis, September 1, 1999; 20(9): 1689 - 1696. [Abstract] [Full Text] [PDF]