Involvement of APC and K-ras mutation in non-polypoid colorectal tumorigenesis


The aim of this study was to clarify the role of APC and K- ras mutations in non-polypoid colorectal tumorigenesis. DNA from 63 adenomas (31 polypoid, 17 superficial elevated, 15 superficial depressed), 66 submucosally invasive carcinomas (47 polypoid, 19 non-polypoid) and 34 advanced carcinomas were examined for K- ras codon 12 point mutations and APC mutations in the mutation cluster region. K- ras mutation: the frequency in superficial depressed adenomas was lower than that in polypoid adenomas (0% vs 31%: P = 0.018). The frequency in non-polypoid carcinomas was lower than that in polypoid carcinomas (11% vs 56%: P = 0.0008), and was relatively low compared with that in polypoid adenomas (11% vs 31%). APC mutation: the frequency in superficial depressed adenomas was lower than that in polypoid adenomas (7% vs 43%: P = 0.016), and that in polypoid carcinomas was similar to that in non-polypoid carcinomas. Polypoid adenomas, polypoid carcinomas and advanced carcinomas had almost the same frequency. There may be some pathway other than the conventional adenoma-carcinoma sequence in development of non-polypoid carcinomas. The precursors of most non-polypoid carcinomas are considered to be de novo or superficial depressed adenomas. In this non-polypoid pathway, APC mutation seems to be requisite but K- ras mutation not. It is possible that new APC mutations are acquired after the development of superficial depressed adenomas. © Copyright 2000 Cancer Research Campaign

Change history

  • 16 November 2011

    This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication


  1. Be'roud C and Soussi T (1996) APC gene: database of germline and somatic mutations in human tumors and cell lines. Nucleic Acids Res 24: 121–124

  2. Bos JL, Fearon ER, Hamilton SR, Verlaan-de Vries M, Van Boom JH, Van der Eb AJ and Vogelstein B (1987) Prevalence of ras gene mutations in human colorectal cancers. Nature 327: 293–297

  3. Goeltz SE, Hamilton SR and Vogelstein B (1985) Purification of DNA from formaldehyde fixed and paraffin embedded human tissue. Biochem Biophys Res Commun 130: 118–126

  4. Gyllensten UB and Erlich HA (1988) Generation of single-stranded DNA by the polymerase chain reaction and its application to direct sequencing of the HLA-DQA locus. Proc Natl Acad Sci USA 85: 7652–7656

  5. Japanese Research Society for Cancer of the Colon and Rectum (1983) General rules for clinical and pathological studies on the cancer of the colon, rectum and anus. Part II. Histopathological classification. Jpn J Surg 13: 574–598

  6. Kinzler KW and Vogelstein B (1996) Lessons from hereditary colorectal cancer. Cell 87: 159–170

  7. Levi S, Urbano-Ispizua A, Gill R, Thomas DM, Gilbertson J, Foster C and Marshall CJ (1991) Multiple K- ras codon 12 mutations in cholangiocarcinomas demonstrated with a sensitive polymerase chain reaction technique. Cancer Res 51: 3497–3502

  8. Miyaki M, Tanaka K, Kikuchi-Yanoshita R, Muraoka M and Konishi M (1995) Familial polyposis: recent advances. Crit Rev Oncol Hematol 19: 1–31

  9. Miyoshi Y, Nagase H, Ando H, Horii A, Ichii S, Nakatsuru S, Aoki T, Miki Y, Mori T and Nakamura Y (1992) Somatic mutations of the APC gene in colorectal tumors: mutation cluster region in the APC gene. Hum Mol Genet 1: 229–233

  10. Morson BC (1968) Precancerous and early malignant lesions of the large intestine. Br J Surg 55: 725–731

  11. Muto T, Bussey HJR and Morson BC (1975) The evolution of cancer of the colon and rectum. Cancer 36: 2251–2270

  12. Oudejans JJ, Slebos RJC, Zoetmulder FAN, Mooi WJ and Rodenhuis S (1991) 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

  13. Powell SM, Zilz N, Beazer-Barclay Y, Bryan TM, Hamilton SR, Thibodeau SN, Vogelstein B and Kinzler KW (1992) APC mutations occur early during colorectal tumorigenesis. Nature 359: 235–237

  14. Shimoda T, Ikegami M, Fujisaki J, Matsui T, Aizawa S and Ishikawa E (1989) Early colorectal carcinoma with special reference to its development de novo. Cancer 64: 1138–1146

  15. Vasen HFA, Mecklin JP, Khan PM and Lynch HT (1991) The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC). Dis Colon Rectum 34: 424–425

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

  17. Yamagata S, Muto T, Uchida Y, Masaki T, Sawada T, Tsuno N and Hirooka T (1994) Lower incidence of K- ras codon 12 mutation in flat colorectal adenomas than in polypoid adenomas. Jap J of Cancer Res 85: 147–151

  18. Yamagata S, Muto T, Uchida Y, Masaki T, Higuchi Y, Sawada T and Hirooka T (1995) Polypoid growth and K- ras codon 12 mutation in colorectal cancer. Cancer 75: 953–957

Download references

Author information

Rights and permissions

From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit

Reprints and Permissions

About this article

Cite this article

Umetani, N., Sasaki, S., Masaki, T. et al. Involvement of APC and K-ras mutation in non-polypoid colorectal tumorigenesis. Br J Cancer 82, 9–15 (2000).

Download citation


  • APC, K- ras
  • tumorigenesis
  • colorectal carcinoma
  • adenoma-carcinoma sequence

Further reading