The cytogenetic and molecular cytogenetic characterization of human solid tumors and hematological malignancies has revealed a non-random distribution of chromosomal aberrations. The complementary use of comparative genomic hybridization (CGH) and spectral karyotyping (SKY) on the same tumors has provided ample evidence that the translocation induced activation of oncogenes is predominantly restricted to leukemias and lymphomas. The results of chromosomal aberrations in solid tumors of epithelial origin are genomic imbalances. Our research is focused on identifying clinically relevant translocations in hematological malignancies and exploring mechanisms and consequences of genomic imbalances in solid tumors. We intend to use SKY for the classification of acute myelogenous leukemia and for the identification of secondary chromosomal aberrations that correlate with resistance to therapy in patients with chronic myelogenous leukemia treated with the tyrosine kinase inhibitor STI571 and correlate the results with those from murine model systems of leukemias and lymphomas. The CGH analysis of more than 500 carcinomas in our laboratory has revealed that genomic imbalances as a result of unbalanced chromosomal translocations or chromosomal gains and losses are the premier cytogenetic event in solid tumors of epithelial origin. CGH analyses will be focused on colorectal adenomas, carcinomas, and metastases, and ovarian carcinomas. Their cytogenetic profiles will then be compared with gene expression analyses in order to further our understanding of the consequences of aneuploidy. Efforts to define the sequence of genetic aberrations during carcinogenesis, explain the biology of tumor progression and establish test systems for novel therapeutics depend increasingly on animal models of human cancer. Murine models of human carcinogenesis are widely used to delineate genetic mechanisms that determine tumor initiation and progression and improved methods for genetic manipulation open new avenues to study biological pathways of tumorigenesis. We have therefore devoted considerable effort to the development of molecular cytogenetic tools for the analyses of chromosomal aberrations in mouse models of human cancer. Karyotype analysis of chemically induced plasmacytomas in mice,11 in lymphomas from ATM or Ku80 deficient animals, and in mice transgenic for c-myc, has provided evidence for the conservation of mechanisms leading to chromosomal aberrations across species boundaries. Our development of molecular cytogenetic methods for the analysis of murine genomes allows us to further contribute to the validation of mouse models of human cancers.
Showing the most recent 10 out of 16 publications
