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. 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, to explain the biology of tumor progression and to 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, and in lymphomas from ATM or Ku80 deficient animals. These analyses helped to define genetic pathways involved in the maintenance of chromosomal integrity and elucidated mechanisms that contribute to chromosomal translocations, e.g., break induced replication. As part of the intramural mouse models of mammary cancer consortium (MMMC), we have analyzed a plethora of mammary gland adenocarcinomas (MMTC-c-myc, MMTV-her2neu, her2neu-ednogeneous promoter, C3SV40Tag, PyV-mT). These analyses have provided evidence for the conservation of mechanisms leading to chromosomal aberrations and to the maintenance of cancer specific patterns of chromosomal aneuploidies 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. The analysis of the PyV-mT mouse model also resulted in the molecular cloning of a septin 9, as a novel oncogene involved in human breast cancers and mouse models thereof.

Agency
National Institute of Health (NIH)
Institute
Division of Clinical Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01SC010298-06
Application #
7068940
Study Section
(GB)
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2004
Total Cost
Indirect Cost
Name
Clinical Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
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