Clinical & Experimental Metastasis

, Volume 7, Issue 4, pp 417–426 | Cite as

Hypomethylation of the human HLA-DRα gene in breast carcinomas and autologous metastases

  • Rafaella Barbieri
  • Anna Paola Rimondi
  • Daniele Buzzoni
  • Leone Luppi
  • Claudio Nastruzzi
  • Patrizia Orlando
  • Roberto Gambari


The methylation pattern of the human HLA-DRα gene was analyzed in normal breast tissues, breast primary tumors and lymphonodal metastases isolated from patients carrying breast carcinomas. In breast adenomas and also in normal tissues (including breast, muscle, brain, sperm and T- and B-lymphocytes), the HLA-DRα gene is hypermethylated at the CCGG and GCGC sites. In all tissues studied, the only constantly unmethylated region is located in the 5′ portion of the gene, near the promoter sequence. Further, the results indicate that the HLA-DRα gene is hypomethylated in carcinomas and in the relative metastatic lymph nodes. It is suggested that hypomethylation of the human HLA-DRα gene could be proposed as a molecular marker of malignant breast tumors.


Adenoma Primary Tumor Molecular Marker Breast Tumor Breast Carcinoma 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. [1]
    Auffray, C., Lillie, J. W., Arnot, D., Kappas, D., andStrominger, J. L., 1984, Isotypic and allotypic variation of human class II histocompatibility antigenα-chain genes.Nature, (London),308, 327–333.Google Scholar
  2. [2]
    Barbieri, R., Piva, R., Baioni, L., Serino, L., Buzzoni, D., Giacomini, P., Natali, P. G., andGambari, R., 1986, Methylation state of CCGG and GCGC sequences of the human HLA-DRα genen in B-lymphocytes and different tissues.European Journal of Cell Biology,16, 25.Google Scholar
  3. [3]
    Bird, A. P., 1986, CpG-rich islands and the function of DNA methylation.Nature (London),321, 209–216.Google Scholar
  4. [4]
    Cooper, D. N., 1983, Eukaryotic DNA methylation.Human Genetics,64, 315.Google Scholar
  5. [5]
    Das, H. K., Laurance, S. K., andWeissman, S. M., 1981, Structure and nucleotide sequence of heavy chain gene of HLA-DR.Proceedings of National Academy of Sciences of the U.S.A.,80, 534–539.Google Scholar
  6. [6]
    Del Senno, L., Degli Uberti, E., Rossi, M., Buzzoni, D., Barbieri, R., Rossi, P., Patracchini, P., Bernardi, F., Marchetti, G., Conconi, F., andGambari, R., 1986, Identification of a c-myc oncogene lacking the exon 1 in the normal cells of a patient carrying a thyroid carcinoma.FEBS Letters,196, 296–300.Google Scholar
  7. [7]
    Doerfler, W., 1983, DNA methylation and gene activity.Annual Review of Biochemistry,52, 93–124.Google Scholar
  8. [8]
    Feimberg, A. P., andVogelstein, B., 1983, Hypomethylation distinguishes genes of some human cancers from their normal counterparts.Nature (London),301, 89–92.Google Scholar
  9. [9]
    Feimberg, P., andVogelstein, B., 1983, Hypomethylation of ras oncogenes in primary human cancers.Biochemical and Biophysical Research Communication,111, 47–54.Google Scholar
  10. [10]
    Flavell, R. A., Allen, L., Burkly, L. C., Sherman, D. H., Waneck, G. L., andWidera, G., 1986, Molecular biology of the H-2 histocompatibility complex.Science,233, 437–443.Google Scholar
  11. [11]
    Gambari, R., Del Senno, L., Barbieri, R., Buzzoni, D., Gustafsson, K., Giacomini, P., andNatali, P. G., 1986, Lack of correlation between hypomethylation and expression of HLA-DRα gene.European Journal of Immunology,16, 365–369.Google Scholar
  12. [12]
    Gambari, R., Barbieri, R., Buzzoni, D., Bernardi, F., Marchetti, G., Amelotti, F., Piva, R., Viola, L., andDel Senno, L., 1986, Human leukemic K562 cells: suppression of hemoglobin accumulation by a monoclonal antibody to human transferrin receptor.Biochimica et Biophysica Acta,886, 203–213.Google Scholar
  13. [13]
    Gambari, R., Barbieri, R., Piva, R., Tecce, R., Fisher, P. B., Giacomini, P., andNatali, P. G., 1987, Regulation of the expression of class II genes of the human major histocompatibility complex in tumor cells.Annals of New York Academy of Sciences,511, 292–307.Google Scholar
  14. [14]
    Gambari, R., Piva, R., Volinia, S., Orlando, P., Nastruzzi, C., Giacomini, P., Natali, P. G., andBarbieri, R., 1988, CG dinucleotides of class II MHC genes are mutations hot-spots.Cytotechnology,1, 133–138.Google Scholar
  15. [15]
    Goelz, S. E., Vogelstein, B., Hamilton, S. R., andFeimberg, A. P., 1985, Hypomethylation of DNA from benign and malignant human colon neoplasms.Science,228, 187–190.Google Scholar
  16. [16]
    Kormans, A. J., Auffray, C., Scamboeck, A. S., aneStrominger, J., 1982, The amino acid sequence and gene organization of the heavy chain of the HLA-DR antigen: homology to immunoglobulins.Proceedings of National Academy of Sciences of the U.S.A.,99, 6013–6017.Google Scholar
  17. [17]
    Larhammar, D., Gustafsson, K., Claesson, L., Bill, P., Wimar, R., Shenning, L., Sundelin, J., Widmark, E., Peterson, P. A., andRask, L., 1982, Alpha chain of HLA-DR transplantation antigens is a member of the same protein superfamily as the immunoglobulin.Cell,30, 153–164.Google Scholar
  18. [18]
    Lee, J. S., Trowsdale, J., Travers, P. J., Carey, J., Grosveld, F., Jenkins, J., andBodmer, W. F., 1982, Sequence of an HLA-DRα chain cDNA clone and intron-exon organization of the corresponding gene.Nature (London),299, 750–752.Google Scholar
  19. [19]
    Levine, F., andPious, D., 1985, Different roles for cytosine methylation in HLA Class II gene expression.Immunogenetics,22, 427–431.Google Scholar
  20. [20]
    Maniatis, T., Fritsch, F., andSambrook, J., 1982,Molecular Cloning. A Laboratory Manual (New York: Cold Spring Harbor Laboratory Publications), pp. 97–403.Google Scholar
  21. [21]
    Peterlin, B. M., Hardy, K. J., andLarsen, A. S., 1987, Chromatin structure of the HLA-DRα gene in different functional state of major histocompatibility complex class II gene expression.Molecular and Cellular Biology,7, 1967–1972.Google Scholar
  22. [22]
    Razin, A., 1984, DNA methylation patterns formation and function.Biochimica et Biophysica Acta,792, 331–342.Google Scholar
  23. [23]
    Reitz, M. S., Mann, D. L., Eiden, M., Trainor, C. D., andClarke, F. M., 1984, DNA methylation and expression of HLA-DRα.Molecular and Cellular Biology,4, 890–895.Google Scholar
  24. [24]
    Schamboeck, A., Korman, A. J., Kamb, A., andStrominger, J. L., 1983, Organization of transcriptional unit of a human class II histocompatibility antigen: HLA-DR heavy chain.Nucleic Acid Research,11, 8663–8675.Google Scholar
  25. [25]
    Southern, E. M., 1975, Detection of specific sequences among DNA fragments separated by gel electrophoresis.Journal of Molecular Biology,98, 503–517.Google Scholar
  26. [26]
    Stetler, D., Grumet, F. C., andErlich, H. A., 1985, Polymorphic restriction endonuclease sites linked to the HLA-DRα gene: localization and use as genetic markers of insulin-dependent diabetes.Proceedings of the National Academy of Sciences of the U.S.A.,82, 8100–8104.Google Scholar
  27. [27]
    Tykocinski, M. L., andMax, E. M., 1984, CG dinucleotide clusters in MHC genes and in 5′ demythlated genes.Nucleic Acid Research,14, 1–4.Google Scholar
  28. [28]
    Van der Ploeg, L. H. T., andFlavell, R. A., 1980, DNA methylation in the humanγδβ-globin locus in erythroid and nonerythroid tissues.Cell,19, 947–958.Google Scholar

Copyright information

© Taylor & Francis Ltd 1989

Authors and Affiliations

  • Rafaella Barbieri
    • 1
  • Anna Paola Rimondi
    • 2
  • Daniele Buzzoni
    • 1
  • Leone Luppi
    • 2
  • Claudio Nastruzzi
    • 3
  • Patrizia Orlando
    • 4
  • Roberto Gambari
    • 1
    • 2
    • 3
    • 4
  1. 1.Instituto di Chimica BiologicaUniversità di FerraraItaly
  2. 2.Istituto di Anatomia Patologica e CitodiagnosticaOspedale Nuovo di RovigoItaly
  3. 3.Dipartimento di Scienze FarmaceuticheUniversità di FerraraItaly
  4. 4.Centro di Studi Biochimici sul Morbo di CooleyFerraraItaly

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