Skip to main content
SpringerLink
Log in

K-ras Mutations in Sporadic Colorectal Tumors in Israel: Unusual High Frequency of Codon 13 Mutations and Evidence for Nonhomogeneous Representation of Mutation Subtypes

  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

Colorectal cancer is one of the most common malignancies in the western world, including Israel. An important step in progression includes induction of activating mutations in the protooncogene K-ras. This event is very frequent and is detected in about 40% of colorectal carcinomas. Previous studies of a variety of genetic disorders revealed unique gene mutation prevalence in Jewish populations, attributed both to differences in genetic background and to variability in environmental exposure. To determine the incidence and molecular subtypes of K-ras mutations in colorectal cancer in Israel, compared with other countries, DNA was isolated from a random collection of 105 colorectal carcinoma samples, and K-ras mutations were detected by an improved designed RFLP and direct sequencing. K-ras sporadic mutations in colorectal cancer in Israel are relatively frequent, with a higher fraction in codon 13 than reported thus far. Comparison with other countries shows a vast heterogeneity in terms of the relative abundance of the affected K-ras codon and in type and representation of specific mutations. The heterogeneous distribution found may be due to a variable genetic background and different environmental factors involved in the initiation and propagation of sporadic colorectal cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. McMichael AJ, Giles GG: Colorectal cancer. In Cancer surveys 19/20: Trends in cancer incidence and mortality. R Doll, JF Fraumeni Jr, CS Muir (eds). Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1994, pp 77–98

    Google Scholar 

  2. Fearon ER, Vogelstein B: A genetic model for colorectal tumorigenesis. Cell 61:759–767, 1990

    Google Scholar 

  3. Vogelstein B, Kinzler KW: The multistep nature of cancer. Trends Genet 9:138–141, 1993

    Google Scholar 

  4. Fearon ER: Human cancer syndromes: Clues to the origin and nature of cancer. Science 278:1043–1050, 1997

    Google Scholar 

  5. Sidransky D: Nucleic acid-based methods for the detection of cancer. Science 278:1054–1058, 1997

    Google Scholar 

  6. Nigro JM, Cho KR, Fearon ER, Kern SE, Ruppert JM, Oliner JD, Kinzler KW, Vogelstein B: Scrambled exons. Cell 64:607–613, 1991

    Google Scholar 

  7. McLellan EA, Owen RA, Stepniewska KA, Sheffield JP, Lemoin NR: High frequency of K-ras mutations in sporadic colorectal adenomas. Gut 34:392–396, 1993

    Google Scholar 

  8. Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, Nakamura Y, White R, Smits AM, Bos JL: Genetic alterations during colorectal-tumor development. N Engl J Med 319:525–532, 1988

    Google Scholar 

  9. Sidransky D, Tokino T, Hamilton SR, Kinzler KW, Levin B, Frost P, Vogelstein B: Identification of ras oncogene mutations in the stool of patients with curable colorectal tumors. Science 256:102–105, 1992

    Google Scholar 

  10. Smith-Ravin J, England J, Talbot IC, Bodmer W: Detection of c-Ki-ras mutations in faecal samples from sporadic colorectal cancer patients. Gut 36:81–86, 1995

    Google Scholar 

  11. Tobi M, Luo FC, Ronai Z: Detection of K-ras mutation in colonic effluent samples from patients without evidence of colorectal carcinoma. J Natl Cancer Inst 86:1007–1010, 1994

    Google Scholar 

  12. Villa E, Dugani A, Rebecchi A, Vignoli A, Grottola A, Butafoco P, Losi L, Perini M, Trande P, Merighi A, Lerose R, Maneti F: Identification of subject at risk for colorectal carcinoma through a test based on K-ras determination in the stool. Gastroenterology 110:1346–1353, 1996

    Google Scholar 

  13. Jen J, Johnson C, Levin B: Molecular approaches for colorectal cancer screening. Eur J Gastroenterol Hepatol 10:213–217, 1998

    Google Scholar 

  14. Lev, Z., Kislitsin, D., Rennert, G, and Lerner, A. Utilization of K-ras mutations identified in stool DNA for the early detection of colorectal cancer. J Cell Biochem 34(suppl):35–39, 2000

    Google Scholar 

  15. Kahn SM, Jiang W, Culbertson TA, Weinstein IB, Williams GM, Tomita N, Ronai Z: Rapid and sensitive nonradioactive detection of mutant K-ras genes via “enriched” PCR amplification. Oncogene 6:1079–1083, 1991

    Google Scholar 

  16. Minamoto T, Yamashita N, Ochiai A, Mai M, Sugimura T, Ronai Z, Esumi H: Mutant K-ras in apparently normal mucosa of colorectal cancer patients. Its potential as a biomarker of colorectal tumorigenesis. Cancer 75:1520–1526, 1995

    Google Scholar 

  17. Schimanski CC, Linnemann U, Berger MR: Sensitive detection of K-ras mutations augments diagnosis of colorectal cancer metastases in the liver. Cancer Res 59:5169–5175, 1999

    Google Scholar 

  18. Arber N, Shapira I, Ratan J, Stern B, Hibshoosh H, Moshkowitz M, Gammon M, Fabian I, Halpern Z: Activation of c-K-ras mutations in human gastrointestinal tumors. Gastroenterology 118:1045–1050, 2000

    Google Scholar 

  19. Wali RK, Skarosi S, Hart J, Zhang Y, Dolan ME, Moschel RC, Nguyen L, Mustafi R, Brasitus TA, Bissonnette M: Inhibition of O(6)-methylguanine–DNA methyltransferase increases azoxymethane-induced colonic tumors in rats. Carcinogenesis 20:2355–2360, 1999

    Google Scholar 

  20. Esteller M, Toyota M, Sanchez-Cespedes M, Capella G, Peinado MA, Watkins DN, Issa JP, Sidransky D, Baylin SB, Herman JG: Inactivation of the DNA repair gene O(6)-methylguanine–DNA methyltransferase by promoter hypermethylation is associated with G to A mutations in K-ras in colorectal tumorigenesis. Cancer Res 60:2368–2371, 2000

    Google Scholar 

  21. Boivin-Angele S, Lefrancois L, Froment O, Spiethoff A, Bogdanffy MS, Wegener K, Wesch H, Barbin A, Bancel B, Trepo C, Bartsch H, Swenberg J, Marion MJ: Ras gene mutations in vinyl chloride-induced liver tumors are carcinogen specific but vary with cell type and species. Int J Cancer:223–227, 2000

  22. Zhuang SM, Cochran C, Goodrow T, Wiseman RW, Soderkvist P: Genetic alterations of p53 and ras genes in 1,3-butadiene-and 2´,3´-dideoxycytidine-induced lymphomas. Cancer Res 57:2710–2714, 1997

    Google Scholar 

  23. Rochlitz CF, Heide I, de KE, Bohmer R, Peter FJ, Neuhaus P, Huhn D, Herrmann R: Position specificity of Ki-ras oncogene mutations during the progression of colorectal carcinoma. Oncology 50:70–76, 1993

    Google Scholar 

  24. Nollau P, Moser C, Weinland G, Wagener C: Detection of K-ras mutations in stools of patients with colorectal cancer by mutant-enriched PCR. Int J Cancer 66:332–336, 1996

    Google Scholar 

  25. Nagata Y, Abe M, Kobayashi K, Yoshida K, Ishibashi T, Naoe T, Nakayama E, Shiku H: Glycine to aspartic acid mutations at codon 13 of the c-Ki-ras gene in human gastrointestinal cancers. Cancer Res 50:480–482, 1990

    Google Scholar 

  26. Miyaki M, Seki M, Okamoto M, Yamanaka A, Maeda Y, Tanaka K, Kikuchi R, Iwama T, Ikeuchi T, Tonomura A: Genetic changes and histopathological types in colorectal tumors from patients with familial adenomatous polyposis. Cancer Res 50:7166–7173, 1990

    Google Scholar 

  27. Kojima M, Konishi F, Tsukamoto T, Yamashita K, Kanazawa K: Ki-ras point mutation in different types of colorectal carcinomas in early stages. Dis Colon Rectum 40:161–167, 1997

    Google Scholar 

  28. Oudejans JJ, Slebos RJ, Zoetmulder FA, Mooi WJ, Rodenhuis S: Differential activation of ras genes by point mutation in human colon cancer with metastases to either lung or liver. Int J Cancer 49:875–879, 1991

    Google Scholar 

  29. Oliva MR, Cabrera T, Esquivias J, Perez-Ayala M, Redondo M, Ruiz-Cabello F, Garrido F: K-ras mutations (codon 12) are not involved in down-regulation of MHC class-I genes in colon carcinomas. Int J Cancer 46:426–431, 1990

    Google Scholar 

  30. Shaw P, Tardy S, Benito E, Obrador A, Costa J: Occurrence of Ki-ras and p53 mutations in primary colorectal tumors. Oncogene 6:2121–2128, 1991

    Google Scholar 

  31. Benhattar J, Losi L, Chaubert P, Givel JC, Costa J: Prognostic significance of K-ras mutations in colorectal carcinoma. Gastroenterology 104:1044–1048, 1993

    Google Scholar 

  32. Morris RG, Curtis LJ, Romanowski P, Hardcastle JD, Jenkins DA, Robinson M, Wyllie AH, Bird CC: Ki-ras mutations in adenomas: A characteristic of cancer-bearing colorectal mucosa. J Pathol 180:357–363, 1996

    Google Scholar 

  33. Bos JL, Fearon ER, Hamilton SR, Verlaan-de VM, van BJ, van der Eb AJ, Vogelstein B: Prevalence of ras gene mutations in human colorectal cancers. Nature 327:293–297, 1987

    Google Scholar 

  34. Burmer GC, Levine DS, Kulander BG, Haggitt RC, Rubin CE, Rabinovitch PS: c-Ki-ras mutations in chronic ulcerative colitis and sporadic colon carcinoma. Gastroenterology 99:416–420, 1990

    Google Scholar 

  35. Burmer GC, Rabinovitch PS, Loeb LA: Frequency and spectrum of c-Ki-ras mutations in human sporadic colon carcinoma, carcinomas arising in ulcerative colitis, and pancreatic adenocarcinoma. Environ Health Perspect 93:27–31, 1991

    Google Scholar 

  36. Jen J, Powell SM, Papadopoulos N, Smith KJ, Hamilton SR, Vogelstein B, Kinzler KW: Molecular determinants of dysplasia in colorectal lesions. Cancer Res 54:5523–5526, 1994

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biology, Technion–Israel Institute of Technology, Haifa, Israel

    Dmitry Kislitsin & Zeev Lev

  2. Department of Pediatrics, Carmel Medical Center, B. Rappaport Faculty of Medicine, Technion–Israel Institute of Technology, Haifa, Israel

    Aaron Lerner

  3. Department of Community Medicine and Epidemiology, Carmel Medical Center, B. Rappaport Faculty of Medicine, Technion–Israel Institute of Technology, Haifa, Israel

    Gad Rennert

Authors
  1. Dmitry Kislitsin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Aaron Lerner
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gad Rennert
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zeev Lev
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kislitsin, D., Lerner, A., Rennert, G. et al. K-ras Mutations in Sporadic Colorectal Tumors in Israel: Unusual High Frequency of Codon 13 Mutations and Evidence for Nonhomogeneous Representation of Mutation Subtypes. Dig Dis Sci 47, 1073–1079 (2002). https://doi.org/10.1023/A:1015090124153

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1015090124153

Search

Navigation