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Proc Natl Acad Sci U S A. Apr 15, 1991; 88(8): 3470–3474.
PMCID: PMC51469

High expression of the DNA methyltransferase gene characterizes human neoplastic cells and progression stages of colon cancer.

Abstract

DNA methylation abnormalities occur consistently in human neoplasia including widespread hypomethylation and more recently recognized local increases in DNA methylation that hold potential for gene inactivation events. To study this imbalance further, we have cloned and localized to chromosome 19 a portion of the human DNA methyltransferase gene that codes for the enzyme catalyzing DNA methylation. Expression of this gene is low in normal human cells, significantly increased (30- to 50-fold by PCR analysis) in virally transformed cells, and strikingly elevated in human cancer cells (several hundredfold). In comparison to colon mucosa from patients without neoplasia, median levels of DNA methyltransferase transcripts are 15-fold increased in histologically normal mucosa from patients with cancers or the benign polyps that can precede cancers, 60-fold increased in the premalignant polyps, and greater than 200-fold increased in the cancers. Thus, increases in DNA methyltransferase gene expression precede development of colonic neoplasia and continue during progression of colonic neoplasms. These increases may play a role in the genetic instability of cancer and mark early events in cell transformation.

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  • Nowell PC. The clonal evolution of tumor cell populations. Science. 1976 Oct 1;194(4260):23–28. [PubMed]
  • Knudson AG., Jr Genetics of human cancer. Annu Rev Genet. 1986;20:231–251. [PubMed]
  • Bishop JM. The molecular genetics of cancer. Science. 1987 Jan 16;235(4786):305–311. [PubMed]
  • Hansen MF, Cavenee WK. Genetics of cancer predisposition. Cancer Res. 1987 Nov 1;47(21):5518–5527. [PubMed]
  • Weinberg RA. Oncogenes, antioncogenes, and the molecular bases of multistep carcinogenesis. Cancer Res. 1989 Jul 15;49(14):3713–3721. [PubMed]
  • Gama-Sosa MA, Slagel VA, Trewyn RW, Oxenhandler R, Kuo KC, Gehrke CW, Ehrlich M. The 5-methylcytosine content of DNA from human tumors. Nucleic Acids Res. 1983 Oct 11;11(19):6883–6894. [PMC free article] [PubMed]
  • Feinberg AP, Vogelstein B. Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature. 1983 Jan 6;301(5895):89–92. [PubMed]
  • Feinberg AP, Vogelstein B. Hypomethylation of ras oncogenes in primary human cancers. Biochem Biophys Res Commun. 1983 Feb 28;111(1):47–54. [PubMed]
  • Jones PA. DNA methylation and cancer. Cancer Res. 1986 Feb;46(2):461–466. [PubMed]
  • Baylin SB, Höppener JW, de Bustros A, Steenbergh PH, Lips CJ, Nelkin BD. DNA methylation patterns of the calcitonin gene in human lung cancers and lymphomas. Cancer Res. 1986 Jun;46(6):2917–2922. [PubMed]
  • Chandler LA, DeClerck YA, Bogenmann E, Jones PA. Patterns of DNA methylation and gene expression in human tumor cell lines. Cancer Res. 1986 Jun;46(6):2944–2949. [PubMed]
  • Baylin SB, Fearon ER, Vogelstein B, de Bustros A, Sharkis SJ, Burke PJ, Staal SP, Nelkin BD. Hypermethylation of the 5' region of the calcitonin gene is a property of human lymphoid and acute myeloid malignancies. Blood. 1987 Aug;70(2):412–417. [PubMed]
  • Jones PA, Buckley JD. The role of DNA methylation in cancer. Adv Cancer Res. 1990;54:1–23. [PubMed]
  • Goelz SE, Vogelstein B, Hamilton SR, Feinberg AP. Hypomethylation of DNA from benign and malignant human colon neoplasms. Science. 1985 Apr 12;228(4696):187–190. [PubMed]
  • Silverman AL, Park JG, Hamilton SR, Gazdar AF, Luk GD, Baylin SB. Abnormal methylation of the calcitonin gene in human colonic neoplasms. Cancer Res. 1989 Jul 1;49(13):3468–3473. [PubMed]
  • Hausheer FH, Rao SN, Gamcsik MP, Kollman PA, Colvin OM, Saxe JD, Nelkin BD, McLennan IJ, Barnett G, Baylin SB. Computational analysis of structural and energetic consequences of DNA methylation. Carcinogenesis. 1989 Jun;10(6):1131–1137. [PubMed]
  • Antequera F, Macleod D, Bird AP. Specific protection of methylated CpGs in mammalian nuclei. Cell. 1989 Aug 11;58(3):509–517. [PubMed]
  • Meehan RR, Lewis JD, McKay S, Kleiner EL, Bird AP. Identification of a mammalian protein that binds specifically to DNA containing methylated CpGs. Cell. 1989 Aug 11;58(3):499–507. [PubMed]
  • de Bustros A, Nelkin BD, Silverman A, Ehrlich G, Poiesz B, Baylin SB. The short arm of chromosome 11 is a "hot spot" for hypermethylation in human neoplasia. Proc Natl Acad Sci U S A. 1988 Aug;85(15):5693–5697. [PMC free article] [PubMed]
  • Scrable HJ, Witte DP, Lampkin BC, Cavenee WK. Chromosomal localization of the human rhabdomyosarcoma locus by mitotic recombination mapping. Nature. 1987 Oct 15;329(6140):645–647. [PubMed]
  • Weissman BE, Saxon PJ, Pasquale SR, Jones GR, Geiser AG, Stanbridge EJ. Introduction of a normal human chromosome 11 into a Wilms' tumor cell line controls its tumorigenic expression. Science. 1987 Apr 10;236(4798):175–180. [PubMed]
  • Antequera F, Boyes J, Bird A. High levels of de novo methylation and altered chromatin structure at CpG islands in cell lines. Cell. 1990 Aug 10;62(3):503–514. [PubMed]
  • Jones PA, Wolkowicz MJ, Rideout WM, 3rd, Gonzales FA, Marziasz CM, Coetzee GA, Tapscott SJ. De novo methylation of the MyoD1 CpG island during the establishment of immortal cell lines. Proc Natl Acad Sci U S A. 1990 Aug;87(16):6117–6121. [PMC free article] [PubMed]
  • Cedar H. DNA methylation and gene activity. Cell. 1988 Apr 8;53(1):3–4. [PubMed]
  • Kautiainen TL, Jones PA. DNA methyltransferase levels in tumorigenic and nontumorigenic cells in culture. J Biol Chem. 1986 Feb 5;261(4):1594–1598. [PubMed]
  • Di Fiore PP, Falco J, Borrello I, Weissman B, Aaronson SA. The calcium signal for BALB/MK keratinocyte terminal differentiation counteracts epidermal growth factor (EGF) very early in the EGF-induced proliferative pathway. Mol Cell Biol. 1988 Feb;8(2):557–563. [PMC free article] [PubMed]
  • Carney DN, Gazdar AF, Bepler G, Guccion JG, Marangos PJ, Moody TW, Zweig MH, Minna JD. Establishment and identification of small cell lung cancer cell lines having classic and variant features. Cancer Res. 1985 Jun;45(6):2913–2923. [PubMed]
  • Gazdar AF, Carney DN, Nau MM, Minna JD. Characterization of variant subclasses of cell lines derived from small cell lung cancer having distinctive biochemical, morphological, and growth properties. Cancer Res. 1985 Jun;45(6):2924–2930. [PubMed]
  • Mabry M, Nakagawa T, Baylin S, Pettengill O, Sorenson G, Nelkin B. Insertion of the v-Ha-ras oncogene induces differentiation of calcitonin-producing human small cell lung cancer. J Clin Invest. 1989 Jul;84(1):194–199. [PMC free article] [PubMed]
  • Bestor T, Laudano A, Mattaliano R, Ingram V. Cloning and sequencing of a cDNA encoding DNA methyltransferase of mouse cells. The carboxyl-terminal domain of the mammalian enzymes is related to bacterial restriction methyltransferases. J Mol Biol. 1988 Oct 20;203(4):971–983. [PubMed]
  • Curran T, Peters G, Van Beveren C, Teich NM, Verma IM. FBJ murine osteosarcoma virus: identification and molecular cloning of biologically active proviral DNA. J Virol. 1982 Nov;44(2):674–682. [PMC free article] [PubMed]
  • Rappolee DA, Mark D, Banda MJ, Werb Z. Wound macrophages express TGF-alpha and other growth factors in vivo: analysis by mRNA phenotyping. Science. 1988 Aug 5;241(4866):708–712. [PubMed]
  • Alonso S, Minty A, Bourlet Y, Buckingham M. Comparison of three actin-coding sequences in the mouse; evolutionary relationships between the actin genes of warm-blooded vertebrates. J Mol Evol. 1986;23(1):11–22. [PubMed]
  • Noonan KE, Beck C, Holzmayer TA, Chin JE, Wunder JS, Andrulis IL, Gazdar AF, Willman CL, Griffith B, Von Hoff DD, et al. Quantitative analysis of MDR1 (multidrug resistance) gene expression in human tumors by polymerase chain reaction. Proc Natl Acad Sci U S A. 1990 Sep;87(18):7160–7164. [PMC free article] [PubMed]
  • Szyf M, Kaplan F, Mann V, Giloh H, Kedar E, Razin A. Cell cycle-dependent regulation of eukaryotic DNA methylase level. J Biol Chem. 1985 Jul 25;260(15):8653–8656. [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]
  • Vogelstein B, Fearon ER, Kern SE, Hamilton SR, Preisinger AC, Nakamura Y, White R. Allelotype of colorectal carcinomas. Science. 1989 Apr 14;244(4901):207–211. [PubMed]
  • Baker SJ, Fearon ER, Nigro JM, Hamilton SR, Preisinger AC, Jessup JM, vanTuinen P, Ledbetter DH, Barker DF, Nakamura Y, et al. Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science. 1989 Apr 14;244(4901):217–221. [PubMed]
  • Fearon ER, Cho KR, Nigro JM, Kern SE, Simons JW, Ruppert JM, Hamilton SR, Preisinger AC, Thomas G, Kinzler KW, et al. Identification of a chromosome 18q gene that is altered in colorectal cancers. Science. 1990 Jan 5;247(4938):49–56. [PubMed]
  • Lipkin M. Biomarkers of increased susceptibility to gastrointestinal cancer: new application to studies of cancer prevention in human subjects. Cancer Res. 1988 Jan 15;48(2):235–245. [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]
  • 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]
  • Davies RJ, Weidema WF, Sandle GI, Palmer L, Deschner EE, DeCosse JJ. Sodium transport in a mouse model of colonic carcinogenesis. Cancer Res. 1987 Sep 1;47(17):4646–4650. [PubMed]
  • Hall PA, Levison DA. Review: assessment of cell proliferation in histological material. J Clin Pathol. 1990 Mar;43(3):184–192. [PMC free article] [PubMed]
  • Lipkin M, Sherlock P, Decosse JJ. Risk factors and preventive measures in the control of cancer of the large intestine. Curr Probl Cancer. 1980 Apr;4(10):1–57. [PubMed]
  • Burt RW, Bishop DT, Cannon LA, Dowdle MA, Lee RG, Skolnick MH. Dominant inheritance of adenomatous colonic polyps and colorectal cancer. N Engl J Med. 1985 Jun 13;312(24):1540–1544. [PubMed]
  • Cannon-Albright LA, Skolnick MH, Bishop DT, Lee RG, Burt RW. Common inheritance of susceptibility to colonic adenomatous polyps and associated colorectal cancers. N Engl J Med. 1988 Sep 1;319(9):533–537. [PubMed]

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