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. 1988 Aug;85(15):5693–5697. doi: 10.1073/pnas.85.15.5693

The short arm of chromosome 11 is a "hot spot" for hypermethylation in human neoplasia.

A de Bustros 1, B D Nelkin 1, A Silverman 1, G Ehrlich 1, B Poiesz 1, S B Baylin 1
PMCID: PMC281826  PMID: 2840671

Abstract

Inactivation of normally expressed genes may play a role in the formation and/or progression of human cancers. Methylation of cytosine in DNA could potentially participate in such alterations of gene expression. Abnormalities in DNA methylation are a consistent feature of human neoplasms, and we now show that these include not only previously recognized widespread genomic hypomethylation, but also regional increases in gene methylation. A hot spot for abnormal methylation of C + G-rich areas has been detected on the short arm of chromosome 11 in an area known to harbor tumor suppressor genes. This change occurs consistently in common forms of human cancer and appears early during the transformation of cells with viruses including members of the human T-cell leukemia (HTLV) family. Furthermore, in one chromosome 11 gene examined, calcitonin, the increased methylation in somatic tumor cells coincides with the presence of an "inactive" chromatin pattern in the transcriptional regulatory area. The increased regional DNA methylation demonstrated may then participate in or mark chromosomal changes associated with gene inactivation events that are central to the genesis and/or progression of human cancers.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alitalo K., Schwab M., Lin C. C., Varmus H. E., Bishop J. M. Homogeneously staining chromosomal regions contain amplified copies of an abundantly expressed cellular oncogene (c-myc) in malignant neuroendocrine cells from a human colon carcinoma. Proc Natl Acad Sci U S A. 1983 Mar;80(6):1707–1711. doi: 10.1073/pnas.80.6.1707. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Barbosa J. A., Kamarck M. E., Biro P. A., Weissman S. M., Ruddle F. H. Identification of human genomic clones coding the major histocompatibility antigens HLA-a2 and HLA-B7 by DNA-mediated gene transfer. Proc Natl Acad Sci U S A. 1982 Oct;79(20):6327–6331. doi: 10.1073/pnas.79.20.6327. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Barker P. E., Rabin M., Watson M., Breg W. R., Ruddle F. H., Verma I. M. Human c-fos oncogene mapped within chromosomal region 14q21----q31. Proc Natl Acad Sci U S A. 1984 Sep;81(18):5826–5830. doi: 10.1073/pnas.81.18.5826. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Baylin S. B., Fearon E. R., Vogelstein B., de Bustros A., Sharkis S. J., Burke P. J., Staal S. P., Nelkin B. D. 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] [Google Scholar]
  5. Baylin S. B., Höppener J. W., de Bustros A., Steenbergh P. H., Lips C. J., Nelkin B. D. DNA methylation patterns of the calcitonin gene in human lung cancers and lymphomas. Cancer Res. 1986 Jun;46(6):2917–2922. [PubMed] [Google Scholar]
  6. Bird A. P. CpG-rich islands and the function of DNA methylation. Nature. 1986 May 15;321(6067):209–213. doi: 10.1038/321209a0. [DOI] [PubMed] [Google Scholar]
  7. Curran T., MacConnell W. P., van Straaten F., Verma I. M. Structure of the FBJ murine osteosarcoma virus genome: molecular cloning of its associated helper virus and the cellular homolog of the v-fos gene from mouse and human cells. Mol Cell Biol. 1983 May;3(5):914–921. doi: 10.1128/mcb.3.5.914. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Dalla-Favera R., Bregni M., Erikson J., Patterson D., Gallo R. C., Croce C. M. Human c-myc onc gene is located on the region of chromosome 8 that is translocated in Burkitt lymphoma cells. Proc Natl Acad Sci U S A. 1982 Dec;79(24):7824–7827. doi: 10.1073/pnas.79.24.7824. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Edbrooke M. R., Parker D., McVey J. H., Riley J. H., Sorenson G. D., Pettengill O. S., Craig R. K. Expression of the human calcitonin/CGRP gene in lung and thyroid carcinoma. EMBO J. 1985 Mar;4(3):715–724. doi: 10.1002/j.1460-2075.1985.tb03688.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Feinberg A. P., Vogelstein B. Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature. 1983 Jan 6;301(5895):89–92. doi: 10.1038/301089a0. [DOI] [PubMed] [Google Scholar]
  11. Feinberg A. P., Vogelstein B. Hypomethylation of ras oncogenes in primary human cancers. Biochem Biophys Res Commun. 1983 Feb 28;111(1):47–54. doi: 10.1016/s0006-291x(83)80115-6. [DOI] [PubMed] [Google Scholar]
  12. Flatau E., Bogenmann E., Jones P. A. Variable 5-methylcytosine levels in human tumor cell lines and fresh pediatric tumor explants. Cancer Res. 1983 Oct;43(10):4901–4905. [PubMed] [Google Scholar]
  13. Fogh J. Cultivation, characterization, and identification of human tumor cells with emphasis on kidney, testis, and bladder tumors. Natl Cancer Inst Monogr. 1978 Dec;(49):5–9. [PubMed] [Google Scholar]
  14. Gama-Sosa M. A., Slagel V. A., Trewyn R. W., Oxenhandler R., Kuo K. C., Gehrke C. W., Ehrlich M. The 5-methylcytosine content of DNA from human tumors. Nucleic Acids Res. 1983 Oct 11;11(19):6883–6894. doi: 10.1093/nar/11.19.6883. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Gazdar A. F., Carney D. N., Nau M. M., Minna J. D. 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] [Google Scholar]
  16. Goelz S. E., Vogelstein B., Hamilton S. R., Feinberg A. P. Hypomethylation of DNA from benign and malignant human colon neoplasms. Science. 1985 Apr 12;228(4696):187–190. doi: 10.1126/science.2579435. [DOI] [PubMed] [Google Scholar]
  17. Graziano S. L., Lehr B. M., Merl S. A., Ehrlich G. D., Moore J. L., Hallinan E. J., Hubbell C., Davey F. R., Vournakis J., Poiesz B. J. Quantitative assay of human T-cell leukemia/lymphoma virus transformation. Cancer Res. 1987 May 1;47(9):2468–2473. [PubMed] [Google Scholar]
  18. Griffin C. A., Baylin S. B. Expression of the c-myb oncogene in human small cell lung carcinoma. Cancer Res. 1985 Jan;45(1):272–275. [PubMed] [Google Scholar]
  19. Groudine M., Conkin K. F. Chromatin structure and de novo methylation of sperm DNA: implications for activation of the paternal genome. Science. 1985 May 31;228(4703):1061–1068. doi: 10.1126/science.2986289. [DOI] [PubMed] [Google Scholar]
  20. Holliday R. The inheritance of epigenetic defects. Science. 1987 Oct 9;238(4824):163–170. doi: 10.1126/science.3310230. [DOI] [PubMed] [Google Scholar]
  21. Höppener J. W., Steenbergh P. H., Zandberg J., Bakker E., Pearson P. L., Geurts van Kessel A. H., Jansz H. S., Lips C. J. Localization of the polymorphic human calcitonin gene on chromosome 11. Hum Genet. 1984;66(4):309–312. doi: 10.1007/BF00287635. [DOI] [PubMed] [Google Scholar]
  22. Jhanwar S. C., Neel B. G., Hayward W. S., Chaganti R. S. Localization of c-ras oncogene family on human germ-line chromosomes. Proc Natl Acad Sci U S A. 1983 Aug;80(15):4794–4797. doi: 10.1073/pnas.80.15.4794. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Jones P. A. DNA methylation and cancer. Cancer Res. 1986 Feb;46(2):461–466. [PubMed] [Google Scholar]
  24. Kautiainen T. L., Jones P. A. DNA methyltransferase levels in tumorigenic and nontumorigenic cells in culture. J Biol Chem. 1986 Feb 5;261(4):1594–1598. [PubMed] [Google Scholar]
  25. Keshet I., Lieman-Hurwitz J., Cedar H. DNA methylation affects the formation of active chromatin. Cell. 1986 Feb 28;44(4):535–543. doi: 10.1016/0092-8674(86)90263-1. [DOI] [PubMed] [Google Scholar]
  26. Knudson A. G., Jr Genetics of human cancer. Annu Rev Genet. 1986;20:231–251. doi: 10.1146/annurev.ge.20.120186.001311. [DOI] [PubMed] [Google Scholar]
  27. Kühn L. C., McClelland A., Ruddle F. H. Gene transfer, expression, and molecular cloning of the human transferrin receptor gene. Cell. 1984 May;37(1):95–103. doi: 10.1016/0092-8674(84)90304-0. [DOI] [PubMed] [Google Scholar]
  28. Lock L. F., Takagi N., Martin G. R. Methylation of the Hprt gene on the inactive X occurs after chromosome inactivation. Cell. 1987 Jan 16;48(1):39–46. doi: 10.1016/0092-8674(87)90353-9. [DOI] [PubMed] [Google Scholar]
  29. McBride O. W., Swan D. C., Santos E., Barbacid M., Tronick S. R., Aaronson S. A. Localization of the normal allele of T24 human bladder carcinoma oncogene to chromosome 11. Nature. 1982 Dec 23;300(5894):773–774. doi: 10.1038/300773a0. [DOI] [PubMed] [Google Scholar]
  30. McClelland A., Kühn L. C., Ruddle F. H. The human transferrin receptor gene: genomic organization, and the complete primary structure of the receptor deduced from a cDNA sequence. Cell. 1984 Dec;39(2 Pt 1):267–274. doi: 10.1016/0092-8674(84)90004-7. [DOI] [PubMed] [Google Scholar]
  31. Miller A. D., Curran T., Verma I. M. c-fos protein can induce cellular transformation: a novel mechanism of activation of a cellular oncogene. Cell. 1984 Jan;36(1):51–60. doi: 10.1016/0092-8674(84)90073-4. [DOI] [PubMed] [Google Scholar]
  32. Miller Y. E., Jones C., Scoggin C., Morse H., Seligman P. Chromosome 3q (22-ter) encodes the human transferrin receptor. Am J Hum Genet. 1983 Jul;35(4):573–583. [PMC free article] [PubMed] [Google Scholar]
  33. Miyoshi I., Kubonishi I., Yoshimoto S., Akagi T., Ohtsuki Y., Shiraishi Y., Nagata K., Hinuma Y. Type C virus particles in a cord T-cell line derived by co-cultivating normal human cord leukocytes and human leukaemic T cells. Nature. 1981 Dec 24;294(5843):770–771. doi: 10.1038/294770a0. [DOI] [PubMed] [Google Scholar]
  34. Neel B. G., Jhanwar S. C., Chaganti R. S., Hayward W. S. Two human c-onc genes are located on the long arm of chromosome 8. Proc Natl Acad Sci U S A. 1982 Dec;79(24):7842–7846. doi: 10.1073/pnas.79.24.7842. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Park J. G., Kramer B. S., Steinberg S. M., Carmichael J., Collins J. M., Minna J. D., Gazdar A. F. Chemosensitivity testing of human colorectal carcinoma cell lines using a tetrazolium-based colorimetric assay. Cancer Res. 1987 Nov 15;47(22):5875–5879. [PubMed] [Google Scholar]
  36. Przepiorka D., Baylin S. B., McBride O. W., Testa J. R., de Bustros A., Nelkin B. D. The human calcitonin gene is located on the short arm of chromosome 11. Biochem Biophys Res Commun. 1984 Apr 30;120(2):493–499. doi: 10.1016/0006-291x(84)91281-6. [DOI] [PubMed] [Google Scholar]
  37. Quan F., Korneluk R. G., Tropak M. B., Gravel R. A. Isolation and characterization of the human catalase gene. Nucleic Acids Res. 1986 Jul 11;14(13):5321–5335. doi: 10.1093/nar/14.13.5321. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Reddy E. P. Nucleotide sequence analysis of the T24 human bladder carcinoma oncogene. Science. 1983 Jun 3;220(4601):1061–1063. doi: 10.1126/science.6844927. [DOI] [PubMed] [Google Scholar]
  39. Saxon P. J., Srivatsan E. S., Stanbridge E. J. Introduction of human chromosome 11 via microcell transfer controls tumorigenic expression of HeLa cells. EMBO J. 1986 Dec 20;5(13):3461–3466. doi: 10.1002/j.1460-2075.1986.tb04670.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Scrable H. J., Witte D. P., Lampkin B. C., Cavenee W. K. Chromosomal localization of the human rhabdomyosarcoma locus by mitotic recombination mapping. Nature. 1987 Oct 15;329(6140):645–647. doi: 10.1038/329645a0. [DOI] [PubMed] [Google Scholar]
  41. Seifter E. J., Sausville E. A., Battey J. Comparison of amplified and unamplified c-myc gene structure and expression in human small cell lung carcinoma cell lines. Cancer Res. 1986 Apr;46(4 Pt 2):2050–2055. [PubMed] [Google Scholar]
  42. Shih C., Weinberg R. A. Isolation of a transforming sequence from a human bladder carcinoma cell line. Cell. 1982 May;29(1):161–169. doi: 10.1016/0092-8674(82)90100-3. [DOI] [PubMed] [Google Scholar]
  43. Shmookler Reis R. J., Goldstein S. Interclonal variation in methylation patterns for expressed and non-expressed genes. Nucleic Acids Res. 1982 Jul 24;10(14):4293–4304. doi: 10.1093/nar/10.14.4293. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Shmookler Reis R. J., Goldstein S. Variability of DNA methylation patterns during serial passage of human diploid fibroblasts. Proc Natl Acad Sci U S A. 1982 Jul;79(13):3949–3953. doi: 10.1073/pnas.79.13.3949. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Sood A. K., Pereira D., Weissman S. M. Isolation and partial nucleotide sequence of a cDNA clone for human histocompatibility antigen HLA-B by use of an oligodeoxynucleotide primer. Proc Natl Acad Sci U S A. 1981 Jan;78(1):616–620. doi: 10.1073/pnas.78.1.616. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Stenman G., Sager R. Genetic analysis of tumorigenesis: a conserved region in the human and Chinese hamster genomes contains genetically identified tumor-suppressor genes. Proc Natl Acad Sci U S A. 1987 Dec;84(24):9099–9102. doi: 10.1073/pnas.84.24.9099. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Sweet R. W., Chao M. V., Axel R. The structure of the thymidine kinase gene promoter: nuclease hypersensitivity correlates with expression. Cell. 1982 Dec;31(2 Pt 1):347–353. doi: 10.1016/0092-8674(82)90128-3. [DOI] [PubMed] [Google Scholar]
  48. Tabin C. J., Bradley S. M., Bargmann C. I., Weinberg R. A., Papageorge A. G., Scolnick E. M., Dhar R., Lowy D. R., Chang E. H. Mechanism of activation of a human oncogene. Nature. 1982 Nov 11;300(5888):143–149. doi: 10.1038/300143a0. [DOI] [PubMed] [Google Scholar]
  49. Weissman B. E., Saxon P. J., Pasquale S. R., Jones G. R., Geiser A. G., Stanbridge E. J. 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. doi: 10.1126/science.3031816. [DOI] [PubMed] [Google Scholar]
  50. White R., Leppert M., Bishop D. T., Barker D., Berkowitz J., Brown C., Callahan P., Holm T., Jerominski L. Construction of linkage maps with DNA markers for human chromosomes. Nature. 1985 Jan 10;313(5998):101–105. doi: 10.1038/313101a0. [DOI] [PubMed] [Google Scholar]
  51. Wolf S. F., Jolly D. J., Lunnen K. D., Friedmann T., Migeon B. R. Methylation of the hypoxanthine phosphoribosyltransferase locus on the human X chromosome: implications for X-chromosome inactivation. Proc Natl Acad Sci U S A. 1984 May;81(9):2806–2810. doi: 10.1073/pnas.81.9.2806. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. de Bustros A., Baylin S. B., Berger C. L., Roos B. A., Leong S. S., Nelkin B. D. Phorbol esters increase calcitonin gene transcription and decrease c-myc mRNA levels in cultured human medullary thyroid carcinoma. J Biol Chem. 1985 Jan 10;260(1):98–104. [PubMed] [Google Scholar]
  53. deBustros A., Baylin S. B., Levine M. A., Nelkin B. D. Cyclic AMP and phorbol esters separately induce growth inhibition, calcitonin secretion, and calcitonin gene transcription in cultured human medullary thyroid carcinoma. J Biol Chem. 1986 Jun 15;261(17):8036–8041. [PubMed] [Google Scholar]
  54. van der Ploeg L. H., Flavell R. A. DNA methylation in the human gamma delta beta-globin locus in erythroid and nonerythroid tissues. Cell. 1980 Apr;19(4):947–958. doi: 10.1016/0092-8674(80)90086-0. [DOI] [PubMed] [Google Scholar]

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