CGH analyses of human tumors have revealed that chromosomal aberrations result in genomic imbalances specific for different tumor from diverse tissue types. Furthermore, these changes define discrete steps in the progression of epithelial tumors. More than 90% of cervical carcinomas carry extra copies of chromosome 3 and virtually all diploid breast cancers show a gain of chromosome 1q. Also, gains of chromosome 3q precede copy number increases of chromosomes 5p and 1, and loss of chromosome 2 during the genesis of cervical carcinomas. It is therefore conducive to apply the visualization of these recurring and specific chromosomal aberrations to complement and enhance the cytomorphological diagnosis of human cancers and their precursor lesions. This can be achieved using interphase cytogenetics with fluorescently tagged DNA probes that recognize specific chromosomal target regions directly in interphase cells. We have focused on three applications: Identification of the progressive potential of cervical intraepithelial neoplasia based on the detection of extra copies of chromosome 3 and 5 in thinprep PAP-smears. Diagnosis and prognostication of suspicious breast lesions following the detection of chromosomal aneuploidies in fine needle aspirates. Visualization of specific chromosomal aneuploidies in cytokeratin positive epithelial cells isolated from the peripheral blood of breast cancer patients. These projects are accompanied by the improvement of procedures for the preparation of cytological specimens for interphase cytogenetics, by the development of directly labeled, multicolor probe cocktails for relevant chromosomal regions, oncogenes, and tumor suppressor genes (supported by a CRADA with Vysis, Inc.), and by the development of semi-automated or automated microscope hardware and imaging software for fluorescent spot counting. We could show that the visualization of chromosomal aneupoloidies in cytological preparations (fine needle aspirates from the breast and monolayer PAP-smears) is highly specific and sensitive tests for the diagnosis of cancer and premalignant precursor lesions.

Agency
National Institute of Health (NIH)
Institute
Division of Clinical Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01SC010300-04
Application #
6758337
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2002
Total Cost
Indirect Cost
Name
Clinical Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Grade, Marian; Becker, Heinz; Liersch, Torsten et al. (2006) Molecular cytogenetics: genomic imbalances in colorectal cancer and their clinical impact. Cell Oncol 28:71-84
Helou, Khalil; Padilla-Nash, Hesed; Wangsa, Danny et al. (2006) Comparative genome hybridization reveals specific genomic imbalances during the genesis from benign through borderline to malignant ovarian tumors. Cancer Genet Cytogenet 170:1-8
Andersson, S; Wallin, K-L; Hellstrom, A-C et al. (2006) Frequent gain of the human telomerase gene TERC at 3q26 in cervical adenocarcinomas. Br J Cancer 95:331-8
Grade, Marian; Ghadimi, B Michael; Varma, Sudhir et al. (2006) Aneuploidy-dependent massive deregulation of the cellular transcriptome and apparent divergence of the Wnt/beta-catenin signaling pathway in human rectal carcinomas. Cancer Res 66:267-82
Heselmeyer-Haddad, Kerstin; Sommerfeld, Kathrin; White, Nicole M et al. (2005) Genomic amplification of the human telomerase gene (TERC) in pap smears predicts the development of cervical cancer. Am J Pathol 166:1229-38
Stoltzfus, P; Heselmeyer-Haddad, K; Castro, J et al. (2005) Gain of chromosome 3q is an early and consistent genetic aberration in carcinomas of the vulva. Int J Gynecol Cancer 15:120-6
Rao, V Koneti; Wangsa, Darawalee; Robey, Robert W et al. (2005) Characterization of ABCG2 gene amplification manifesting as extrachromosomal DNA in mitoxantrone-selected SF295 human glioblastoma cells. Cancer Genet Cytogenet 160:126-33
Barenboim-Stapleton, Linda; Yang, Xuezhong; Tsokos, Maria et al. (2005) Pediatric pancreatoblastoma: histopathologic and cytogenetic characterization of tumor and derived cell line. Cancer Genet Cytogenet 157:109-17
Kronenwett, U; Huwendiek, S; Castro, J et al. (2005) Characterisation of breast fine-needle aspiration biopsies by centrosome aberrations and genomic instability. Br J Cancer 92:389-95
Ghadimi, B Michael; Grade, Marian; Difilippantonio, Michael J et al. (2005) Effectiveness of gene expression profiling for response prediction of rectal adenocarcinomas to preoperative chemoradiotherapy. J Clin Oncol 23:1826-38

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