Dr. Thomas Ried
Genetics Department, Division of Clinical Sciences, National Cancer Institute/NIH, Bldg. 9, Rm.
1N 105- 9 Memorial Drive - MSC 0913 - Bethesda, MD 20892-0913
(Tel: 301-402-2008 Fax: 301-435-4428 Email: riedt@mail.nih.gov)
Chromosomal aberrations are key events in the initiation and progression of cancer and can be detected in virtually all tumors. We will discuss novel molecular cytogenetic tools for the visualization of both balanced, reciprocal as well as numerical chromosomal aberrations that induce aneuploidy in cancer cells. Such recent improvements of molecular cytogenetic techniques include comparative genomic hybridization (CGH) and spectral karyotyping (SKY); both techniques allow for the survey of tumor genomes for chromosomal aberrations in a single experiment and permit identification of tumor specific chromosomal aberrations with unprecedented accuracy.
Comparative genomic hybridization is an ideal tool to analyze chromosomal imbalances in archived tumor material and to correlate these findings with tumor phenotypes. CGH analyses of large series of carcinomas revealed a pattern of chromosomal aberrations that is (i) highly specific for the different tumors, (ii) specific for discrete stages during progression, and (iii) indicates increased genetic instability during tumor progression. SKY is based on the simultaneous hybridization of differentially labeled chromosome painting probes, followed by spectral imaging that allows the unique display of all human and murine chromosomes in different colors. We will discuss the value of SKY for the identification of patterns of chromosomal aberrations in hematological malignancies and solid tumors and explore the usefulness of cytogenetics techniques for the validation of mouse models of human cancer. Indeed, the comparison of chromosomal gains and losses and chromosomal breakpoints may assist in the identification of genomic alterations that are relevant for tumorigenesis across species boundaries.
Because the predominance of numerical chromosomal aberrations in solid tumors of epithelial origin (carcinomas) suggest that aneuploidy and therefore the acquisition of genomic imbalances are the premier cytogenetic abnormality in solid tumors the role of chromosome segregation errors and the involvement of abnormalities of the centrosome as the major organizer of the mitotic spindle apparatus will be discussed.
References:
Schrbck, E., du Manoir, S., Veldman, T., Schoell, B., Wienberg, J., Ferguson-Smith, M.A., Ning, Y., Ledbetter, D.H., Soenksen, D., Garini, Y., and Ried, T. (1996). Multicolor spectral karyotyping of human chromosomes. Science 273:494-497.
Liyanage, M., Coleman, A., du Manoir, S., Veldman, T., McCormack, S., Dickson, R.B., Barlow, C., Wynshaw-Boris, A., Janz, S., Wienberg, J., Ferguson-Smith, M.A., Schrdck, E., and Ried, T. (1996). Multicolour spectral karyotyping of mouse chromosomes. Nature Genet. 14:312-315.
Ried, T., Heselmeyer-Haddad, K., Blegen, H., Schrdck, E., and Auer, G. (1999). Genomic changes defining genesis, progression, and malignancy potential in human solid tumors: A phenotype/genotype correlation. Genes Chromosom. Cancer 25:195-204.
Weaver, Z., McCormack, S., Liyanage, M., duManoir, S., Schrdck, E., Dickson, R.B., and Ried, T. (1999). A recurring pattern of chromosomal aberrations in mammary gland tumors of MMTV-cmyc transgenic mice. Genes Chromosom. Cancer 25:25 1-260.
Ghadimi, B.M., Sackett, D.L., Difilippantonio, M.J., Schrdck, E., Jauho, A., Neumann, T., Jauho, A., Auer, G., and Ried, T. (2000). Centrosome amplification and instability occurs exclusively in aneuploid, but not in diploid colorectal cancer cell lines and correlates with numerical chromosomal aberrations. Genes Chromosom. Cancer. 27: 183-190.
Difilippantonio, M., Zhu, J., Chen, H.T., Meffre, E., Nussenzweig, M.C., Max, E., Ried, T., and Nussenzweig, A. (2000). DNA repair protein Ku80 suppresses chromosomal aberrations and malignant transformation. Nature 404:510-514.
Kirsch, I.R., Green, E.D., Yonescu, R., Strausberg, R.L., Carter, N.P., Bentley, D., Leversha, M.A., Dunham, I., Braden, V.V., Hilgenfeld, E., Schuler, G.D., Lash, A.E., Shen, G.L., Martelli, M., Kuehl, W.M., Klausner, R.D., and Ried, T. (2000). A systematic, high-resolution linkage of the cytogenetic and physical maps of the human genome: The Cancer chromosome aberration project (Ccap). Nature Genet. 24:339-340.
Liyanage, M., Weaver, Z., Barlow, C., Coleman, A., Pankratz, D.G., Anderson, S., Wynshaw-Boris, A., and Ried, T. (2000). Abnormal rearrangement within the alpha/delta T-cell receptor locus in lymphomas from ATM-deficient mice. Blood 96:1940-1946.
Thomas Ried, M.D.Section Chief, Unit of Fluorescence in situ Hybridization Techniques National Cancer Institute/ National Institutes of Health
1989 M.D. Molecular Biology, University of Heidelberg, Germany
1995 Habilitation Human Genetics, University of Heidelberg, Germany
RESEARCH EXPERIENCE
August 1992-May 1994: Department of Human Genetics, University of Heidelberg. Germany (Dr. Thomas Cremer),
September 1990-July 1992: Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA (Dr. David C. Ward)
PROFESSIONAL APPOINTMENTS
February 2000: Tenure at National Institutes of Health
October 1998: Principle Investigator: National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
January 1998: Co-Director (with Dr. Ilan R. Kirch), Cancer Chromosome Aberration Project(C-cap), National Cancer Institute, National Institutes of Health (Development of a clone repository and cancer chromosome aberration database).
June 1996: Director, Cytogenctic Core, National Human Genome Research Institute.
June 1994: Head, Unit of Fluorescence in situ Hybridization Techniques, Genome Technology Branch, National Human Genome Research Institutes, National Institutes of Health, Bethesda, Maryland.