Abstract
The series of genetic changes leading to malignancy in colorectal cancer is well reported. This includes mutational activation of the proto-oncogene Ki-ras and mutation/deletion of the p53 tumour suppressor gene. The frequency of these mutations was investigated in a panel of 52 colorectal cancer patients using a combination of immunocytochemistry and non-radioactive, digoxigenin-labelled in situ hybridisation. Sixty two per cent (32 of 52) of the study population were positive for p53 overexpression and 36% (19 of 52) positive for Ki-ras mutation. Twenty seven per cent (14 of 52) of the patients expressed both mutations. Mutation of either the p53 or the Ki-ras gene did not correlate with Dukes's stage, tumour differentiation or 5 year survival rate of the patients. Most of the rectal carcinoma specimens (11 of 15) showed p53 over-expression but the significance of this was not supported statistically. Thus detection of molecular changes is becoming more amenable to incorporation into routine histological carcinoma assessment because of the advent of non-radioactive labelling in in situ hybridisation and antibodies suitable for paraffin wax embedded specimens. The significance of these mutations in disease prognosis, however, remains questionable.
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- Baker S. J., Fearon E. R., Nigro J. M., Hamilton S. R., Preisinger A. C., Jessup J. M., vanTuinen P., Ledbetter D. H., Barker D. F., Nakamura Y. Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science. 1989 Apr 14;244(4901):217–221. doi: 10.1126/science.2649981. [DOI] [PubMed] [Google Scholar]
- Bell S. M., Kelly S. A., Hoyle J. A., Lewis F. A., Taylor G. R., Thompson H., Dixon M. F., Quirke P. c-Ki-ras gene mutations in dysplasia and carcinomas complicating ulcerative colitis. Br J Cancer. 1991 Jul;64(1):174–178. doi: 10.1038/bjc.1991.264. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bell S. M., Scott N., Cross D., Sagar P., Lewis F. A., Blair G. E., Taylor G. R., Dixon M. F., Quirke P. Prognostic value of p53 overexpression and c-Ki-ras gene mutations in colorectal cancer. Gastroenterology. 1993 Jan;104(1):57–64. doi: 10.1016/0016-5085(93)90835-z. [DOI] [PubMed] [Google Scholar]
- Bodmer W. F., Bailey C. J., Bodmer J., Bussey H. J., Ellis A., Gorman P., Lucibello F. C., Murday V. A., Rider S. H., Scambler P. Localization of the gene for familial adenomatous polyposis on chromosome 5. Nature. 1987 Aug 13;328(6131):614–616. doi: 10.1038/328614a0. [DOI] [PubMed] [Google Scholar]
- Cunningham J., Lust J. A., Schaid D. J., Bren G. D., Carpenter H. A., Rizza E., Kovach J. S., Thibodeau S. N. Expression of p53 and 17p allelic loss in colorectal carcinoma. Cancer Res. 1992 Apr 1;52(7):1974–1980. [PubMed] [Google Scholar]
- Dati C., Muraca R., Tazartes O., Antoniotti S., Perroteau I., Giai M., Cortese P., Sismondi P., Saglio G., De Bortoli M. c-erbB-2 and ras expression levels in breast cancer are correlated and show a co-operative association with unfavorable clinical outcome. Int J Cancer. 1991 Apr 1;47(6):833–838. doi: 10.1002/ijc.2910470607. [DOI] [PubMed] [Google Scholar]
- De Benedetti L., Varesco L., Pellegata N. S., Losi L., Gismondi V., Casarino L., Sciallero S., Bonelli L., Biticchi R., Bafico A. Genetic events in sporadic colorectal adenomas: K-ras and p53 heterozygous mutations are not sufficient for malignant progression. Anticancer Res. 1993 May-Jun;13(3):667–670. [PubMed] [Google Scholar]
- Donehower L. A., Bradley A. The tumor suppressor p53. Biochim Biophys Acta. 1993 Aug 23;1155(2):181–205. doi: 10.1016/0304-419x(93)90004-v. [DOI] [PubMed] [Google Scholar]
- Enomoto T., Fujita M., Inoue M., Rice J. M., Nakajima R., Tanizawa O., Nomura T. Alterations of the p53 tumor suppressor gene and its association with activation of the c-K-ras-2 protooncogene in premalignant and malignant lesions of the human uterine endometrium. Cancer Res. 1993 Apr 15;53(8):1883–1888. [PubMed] [Google Scholar]
- Fearon E. R., Cho K. R., Nigro J. M., Kern S. E., Simons J. W., Ruppert J. M., Hamilton S. R., Preisinger A. C., Thomas G., Kinzler K. W. Identification of a chromosome 18q gene that is altered in colorectal cancers. Science. 1990 Jan 5;247(4938):49–56. doi: 10.1126/science.2294591. [DOI] [PubMed] [Google Scholar]
- Feig L. A. The many roads that lead to Ras. Science. 1993 May 7;260(5109):767–768. doi: 10.1126/science.8484117. [DOI] [PubMed] [Google Scholar]
- Feinberg A. P., Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. doi: 10.1016/0003-2697(83)90418-9. [DOI] [PubMed] [Google Scholar]
- Forrester K., Almoguera C., Han K., Grizzle W. E., Perucho M. Detection of high incidence of K-ras oncogenes during human colon tumorigenesis. 1987 May 28-Jun 3Nature. 327(6120):298–303. doi: 10.1038/327298a0. [DOI] [PubMed] [Google Scholar]
- Going J. J., Anderson T. J., Wyllie A. H. Ras p21 in breast tissue: associations with pathology and cellular localisation. Br J Cancer. 1992 Jan;65(1):45–50. doi: 10.1038/bjc.1992.9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hollstein M., Sidransky D., Vogelstein B., Harris C. C. p53 mutations in human cancers. Science. 1991 Jul 5;253(5015):49–53. doi: 10.1126/science.1905840. [DOI] [PubMed] [Google Scholar]
- Horio Y., Takahashi T., Kuroishi T., Hibi K., Suyama M., Niimi T., Shimokata K., Yamakawa K., Nakamura Y., Ueda R. Prognostic significance of p53 mutations and 3p deletions in primary resected non-small cell lung cancer. Cancer Res. 1993 Jan 1;53(1):1–4. [PubMed] [Google Scholar]
- Huang Y., Meltzer S. J., Yin J., Tong Y., Chang E. H., Srivastava S., McDaniel T., Boynton R. F., Zou Z. Q. Altered messenger RNA and unique mutational profiles of p53 and Rb in human esophageal carcinomas. Cancer Res. 1993 Apr 15;53(8):1889–1894. [PubMed] [Google Scholar]
- Kinzler K. W., Nilbert M. C., Su L. K., Vogelstein B., Bryan T. M., Levy D. B., Smith K. J., Preisinger A. C., Hedge P., McKechnie D. Identification of FAP locus genes from chromosome 5q21. Science. 1991 Aug 9;253(5020):661–665. doi: 10.1126/science.1651562. [DOI] [PubMed] [Google Scholar]
- Lane D. P. Cancer. p53, guardian of the genome. Nature. 1992 Jul 2;358(6381):15–16. doi: 10.1038/358015a0. [DOI] [PubMed] [Google Scholar]
- Leppert M., Dobbs M., Scambler P., O'Connell P., Nakamura Y., Stauffer D., Woodward S., Burt R., Hughes J., Gardner E. The gene for familial polyposis coli maps to the long arm of chromosome 5. Science. 1987 Dec 4;238(4832):1411–1413. doi: 10.1126/science.3479843. [DOI] [PubMed] [Google Scholar]
- Lu X., Park S. H., Thompson T. C., Lane D. P. Ras-induced hyperplasia occurs with mutation of p53, but activated ras and myc together can induce carcinoma without p53 mutation. Cell. 1992 Jul 10;70(1):153–161. doi: 10.1016/0092-8674(92)90541-j. [DOI] [PubMed] [Google Scholar]
- Maestro R., Viel A., Boiocchi M. Correlation between chromosome 5q deletions and different mechanisms of c-myc overexpression in human colorectal cancer. Br J Cancer. 1991 Feb;63(2):185–186. doi: 10.1038/bjc.1991.45. [DOI] [PMC free article] [PubMed] [Google Scholar]
- McCoy M. S., Bargmann C. I., Weinberg R. A. Human colon carcinoma Ki-ras2 oncogene and its corresponding proto-oncogene. Mol Cell Biol. 1984 Aug;4(8):1577–1582. doi: 10.1128/mcb.4.8.1577. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Meltzer S. J., Mane S. M., Wood P. K., Resau J. H., Newkirk C., Terzakis J. A., Korelitz B. I., Weinstein W. M., Needleman S. W. Activation of c-Ki-ras in human gastrointestinal dysplasias determined by direct sequencing of polymerase chain reaction products. Cancer Res. 1990 Jun 15;50(12):3627–3630. [PubMed] [Google Scholar]
- Mitsudomi T., Oyama T., Gazdar A. F., Minna J. D., Okabayashi K., Shirakusa T. [Mutations of ras and p53 genes in human non-small cell lung cancer cell lines and their clinical significance]. Nihon Geka Gakkai Zasshi. 1992 Sep;93(9):944–947. [PubMed] [Google Scholar]
- Poller D. N., Hutchings C. E., Galea M., Bell J. A., Nicholson R. A., Elston C. W., Blamey R. W., Ellis I. O. p53 protein expression in human breast carcinoma: relationship to expression of epidermal growth factor receptor, c-erbB-2 protein overexpression, and oestrogen receptor. Br J Cancer. 1992 Sep;66(3):583–588. doi: 10.1038/bjc.1992.318. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Reiter R. E., Anglard P., Liu S., Gnarra J. R., Linehan W. M. Chromosome 17p deletions and p53 mutations in renal cell carcinoma. Cancer Res. 1993 Jul 1;53(13):3092–3097. [PubMed] [Google Scholar]
- Remvikos Y., Tominaga O., Hammel P., Laurent-Puig P., Salmon R. J., Dutrillaux B., Thomas G. Increased p53 protein content of colorectal tumours correlates with poor survival. Br J Cancer. 1992 Oct;66(4):758–764. doi: 10.1038/bjc.1992.352. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Scott N., Bell S. M., Sagar P., Blair G. E., Dixon M. F., Quirke P. p53 expression and K-ras mutation in colorectal adenomas. Gut. 1993 May;34(5):621–624. doi: 10.1136/gut.34.5.621. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Scott N., Quirke P. Molecular biology of colorectal neoplasia. Gut. 1993 Mar;34(3):289–292. doi: 10.1136/gut.34.3.289. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Scott N., Sagar P., Stewart J., Blair G. E., Dixon M. F., Quirke P. p53 in colorectal cancer: clinicopathological correlation and prognostic significance. Br J Cancer. 1991 Feb;63(2):317–319. doi: 10.1038/bjc.1991.74. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Stahl J. A., Leone A., Rosengard A. M., Porter L., King C. R., Steeg P. S. Identification of a second human nm23 gene, nm23-H2. Cancer Res. 1991 Jan 1;51(1):445–449. [PubMed] [Google Scholar]
- Starzynska T., Bromley M., Ghosh A., Stern P. L. Prognostic significance of p53 overexpression in gastric and colorectal carcinoma. Br J Cancer. 1992 Sep;66(3):558–562. doi: 10.1038/bjc.1992.314. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Suchy B., Zietz C., Rabes H. M. K-ras point mutations in human colorectal carcinomas: relation to aneuploidy and metastasis. Int J Cancer. 1992 Aug 19;52(1):30–33. doi: 10.1002/ijc.2910520107. [DOI] [PubMed] [Google Scholar]
- Teneriello M. G., Ebina M., Linnoila R. I., Henry M., Nash J. D., Park R. C., Birrer M. J. p53 and Ki-ras gene mutations in epithelial ovarian neoplasms. Cancer Res. 1993 Jul 1;53(13):3103–3108. [PubMed] [Google Scholar]
- Vogelstein B., Fearon E. R., Hamilton S. R., Kern S. E., Preisinger A. C., Leppert M., Nakamura Y., White R., Smits A. M., Bos J. L. Genetic alterations during colorectal-tumor development. N Engl J Med. 1988 Sep 1;319(9):525–532. doi: 10.1056/NEJM198809013190901. [DOI] [PubMed] [Google Scholar]
- Walker R. A., Wilkinson N. p21 ras protein expression in benign and malignant human breast. J Pathol. 1988 Oct;156(2):147–153. doi: 10.1002/path.1711560209. [DOI] [PubMed] [Google Scholar]
- Yamaguchi A., Nakagawara G., Kurosaka Y., Nishimura G., Yonemura Y., Miyazaki I. p53 immunoreaction in endoscopic biopsy specimens of colorectal cancer, and its prognostic significance. Br J Cancer. 1993 Aug;68(2):399–402. doi: 10.1038/bjc.1993.348. [DOI] [PMC free article] [PubMed] [Google Scholar]