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Proc Natl Acad Sci U S A. 1989 Apr; 86(7): 2403–2407.
PMCID: PMC286921

Mutations in the KRAS2 oncogene during progressive stages of human colon carcinoma.


A series of colon carcinomas, adenomas, and adjacent tissues were analyzed for ploidy alterations and mutations in KRAS2. To increase the sensitivity for identifying mutations, we used histological enrichment, cell sorting, and DNA amplification by the polymerase-catalyzed chain reaction followed by direct DNA sequence analysis. Of the 40 carcinomas analyzed, 27 contained aneuploid cells and 26 contained mutations at the first position of codon 12 of KRAS2. Of the 12 adenomas studied, 4 contained aneuploid cells and 9 contained the same mutation at codon 12. In both adenomas and carcinomas, mutations were identified in both diploid and aneuploid cells. In some cases, regions of histologically benign mucosa adjacent to the carcinoma contained mutations. These combined results suggest that mutations in KRAS2 occur early in the development of human colon carcinoma, before change in ploidy, and that these mutations exist in diploid cells from which an aneuploid subpopulation arises. Furthermore, mutations may exist in histologically normal mucosa in regions adjacent to carcinoma, suggesting that a field of genetically abnormal mucosa may surround these tumors.

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  • Morson BC. Genesis of colorectal cancer. Clin Gastroenterol. 1976 Sep;5(3):505–525. [PubMed]
  • Nowell PC. The clonal evolution of tumor cell populations. Science. 1976 Oct 1;194(4260):23–28. [PubMed]
  • Nowell PC. Mechanisms of tumor progression. Cancer Res. 1986 May;46(5):2203–2207. [PubMed]
  • Fearon ER, Hamilton SR, Vogelstein B. Clonal analysis of human colorectal tumors. Science. 1987 Oct 9;238(4824):193–197. [PubMed]
  • Barbacid M. ras genes. Annu Rev Biochem. 1987;56:779–827. [PubMed]
  • Bos JL, Fearon ER, Hamilton SR, Verlaan-de Vries M, van Boom JH, van der Eb AJ, Vogelstein B. Prevalence of ras gene mutations in human colorectal cancers. Nature. 327(6120):293–297. [PubMed]
  • Forrester K, Almoguera C, Han K, Grizzle WE, Perucho M. Detection of high incidence of K-ras oncogenes during human colon tumorigenesis. Nature. 327(6120):298–303. [PubMed]
  • 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. 1988 Sep 1;319(9):525–532. [PubMed]
  • Bos JL, Verlaan-de Vries M, van der Eb AJ, Janssen JW, Delwel R, Löwenberg B, Colly LP. Mutations in N-ras predominate in acute myeloid leukemia. Blood. 1987 Apr;69(4):1237–1241. [PubMed]
  • Farr CJ, Saiki RK, Erlich HA, McCormick F, Marshall CJ. Analysis of RAS gene mutations in acute myeloid leukemia by polymerase chain reaction and oligonucleotide probes. Proc Natl Acad Sci U S A. 1988 Mar;85(5):1629–1633. [PMC free article] [PubMed]
  • Almoguera C, Shibata D, Forrester K, Martin J, Arnheim N, Perucho M. Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell. 1988 May 20;53(4):549–554. [PubMed]
  • Fujita J, Kraus MH, Onoue H, Srivastava SK, Ebi Y, Kitamura Y, Rhim JS. Activated H-ras oncogenes in human kidney tumors. Cancer Res. 1988 Sep 15;48(18):5251–5255. [PubMed]
  • Lemoine NR, Mayall ES, Wyllie FS, Farr CJ, Hughes D, Padua RA, Thurston V, Williams ED, Wynford-Thomas D. Activated ras oncogenes in human thyroid cancers. Cancer Res. 1988 Aug 15;48(16):4459–4463. [PubMed]
  • Taylor IW. A rapid single step staining technique for DNA analysis by flow microfluorimetry. J Histochem Cytochem. 1980 Sep;28(9):1021–1024. [PubMed]
  • Hedley DW, Friedlander ML, Taylor IW, Rugg CA, Musgrove EA. Method for analysis of cellular DNA content of paraffin-embedded pathological material using flow cytometry. J Histochem Cytochem. 1983 Nov;31(11):1333–1335. [PubMed]
  • Rabinovitch PS, Reid BJ, Haggitt RC, Norwood TH, Rubin CE. Progression to cancer in Barrett's esophagus is associated with genomic instability. Lab Invest. 1989 Jan;60(1):65–71. [PubMed]
  • Goelz SE, Hamilton SR, Vogelstein B. Purification of DNA from formaldehyde fixed and paraffin embedded human tissue. Biochem Biophys Res Commun. 1985 Jul 16;130(1):118–126. [PubMed]
  • Mullis KB, Faloona FA. Specific synthesis of DNA in vitro via a polymerase-catalyzed chain reaction. Methods Enzymol. 1987;155:335–350. [PubMed]
  • Saiki RK, Scharf S, Faloona F, Mullis KB, Horn GT, Erlich HA, Arnheim N. Enzymatic amplification of beta-globin genomic sequences and restriction site analysis for diagnosis of sickle cell anemia. Science. 1985 Dec 20;230(4732):1350–1354. [PubMed]
  • Shibata DK, Arnheim N, Martin WJ. Detection of human papilloma virus in paraffin-embedded tissue using the polymerase chain reaction. J Exp Med. 1988 Jan 1;167(1):225–230. [PMC free article] [PubMed]
  • Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. [PMC free article] [PubMed]
  • Monnat RJ, Jr, Maxwell CL, Loeb LA. Nucleotide sequence preservation of human leukemic mitochondrial DNA. Cancer Res. 1985 Apr;45(4):1809–1814. [PubMed]
  • Schmid K, Thomm M, Laminet A, Laue FG, Kessler C, Stetter KO, Schmitt R. Three new restriction endonucleases MaeI, MaeII and MaeIII from Methanococcus aeolicus. Nucleic Acids Res. 1984 Mar 26;12(6):2619–2628. [PMC free article] [PubMed]
  • Tsuchida N, Ryder T, Ohtsubo E. Nucleotide sequence of the oncogene encoding the p21 transforming protein of Kirsten murine sarcoma virus. Science. 1982 Sep 3;217(4563):937–939. [PubMed]
  • Stowers SJ, Glover PL, Reynolds SH, Boone LR, Maronpot RR, Anderson MW. Activation of the K-ras protooncogene in lung tumors from rats and mice chronically exposed to tetranitromethane. Cancer Res. 1987 Jun 15;47(12):3212–3219. [PubMed]
  • Armitage NC, Robins RA, Evans DF, Turner DR, Baldwin RW, Hardcastle JD. The influence of tumour cell DNA abnormalities on survival in colorectal cancer. Br J Surg. 1985 Oct;72(10):828–830. [PubMed]
  • Banner BF, Tomas-De La Vega JE, Roseman DL, Coon JS. Should flow cytometric DNA analysis precede definitive surgery for colon carcinoma? Ann Surg. 1985 Dec;202(6):740–744. [PMC free article] [PubMed]
  • Finan PJ, Quirke P, Dixon MF, Dyson JE, Giles GR, Bird CC. Is DNA aneuploidy a good prognostic indicator in patients with advanced colorectal cancer? Br J Cancer. 1986 Aug;54(2):327–330. [PMC free article] [PubMed]
  • Tribukait B, Hammarberg C, Rubio C. Ploidy and proliferation patterns in colo-rectal adenocarcinomas related to Dukes' classification and to histopathological differentiation. A flow-cytometric DNA study. Acta Pathol Microbiol Immunol Scand A. 1983 Mar;91(2):89–95. [PubMed]
  • Terpstra OT, van Blankenstein M, Dees J, Eilers GA. Abnormal pattern of cell proliferation in the entire colonic mucosa of patients with colon adenoma or cancer. Gastroenterology. 1987 Mar;92(3):704–708. [PubMed]
  • Deschner EE, Maskens AP. Significance of the labeling index and labeling distribution as kinetic parameters in colorectal mucosa of cancer patients and DMH treated animals. Cancer. 1982 Sep 15;50(6):1136–1141. [PubMed]
  • Bleiberg H, Buyse M, Galand P. Cell kinetic indicators of premalignant stages of colorectal cancer. Cancer. 1985 Jul 1;56(1):124–129. [PubMed]
  • Lipkin M. Biomarkers of increased susceptibility to gastrointestinal cancer. Their development and application to studies of cancer prevention. Gastroenterology. 1987 Apr;92(4):1083–1086. [PubMed]
  • ASTLER VB, COLLER FA. The prognostic significance of direct extension of carcinoma of the colon and rectum. Ann Surg. 1954 Jun;139(6):846–852. [PMC free article] [PubMed]

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