The goal of this proposal is to continue to develop and evaluate fluorescence in situ hybridization (FISH) and associated analytical techniques for detection and characterization of chromosomal abnormalities relevant to research and clinical questions of human malignancy. We will focus on detection of low frequency structural and numerical abnormalities in residual disease and disease progression in chronic myelogenous leukemia (CML), and detection and characterization of structural abnormalities in breast cancer. In both diseases, we will determine genetic status and immunophenotype for individual interphase cells. We will: A) Develop multi-color FISH to permit analysis of simultaneous hybridizations using probes for at least 7 different targets. B) Develop hardware and software for computer assisted microscopy to allow convenient analysis of 7 probe hybridizations, automatic slide scanning and recognition of cancer-specific genotypes, and double pass scanning and analysis for sequentially determining cell immunophenotype and genotype. C) Acquire or develop improved probes spanning the BCR and ABL breakpoint regions of chromosomes 9 and 22 involved in CML; and a set of probes distributed along chromosome 17 at about 4 Mb intervals, with additional elements targeted at specific genes implicated in breast cancer. The utility of these probe sets for genetic and phenotypic analysis of CML and breast cancer will be evaluated: A) CML. We will determine the lowest frequency of residual leukemic cells that can be detected by hybridization to interphase cells, determine the frequency, phenotype and proliferation status of residual leukemic cells in patients undergoing interferon therapy, and determine how early genetic progression characteristic of CML blast crisis can be detected. B) Breast Cancer. We will test the ability of the chromosome 17 probe set to detect structural abnormalities in cell lines, breast tumors, potential precursor lesions, and metastases. We will study the spatial distribution of heterogeneity and clonality in breast cancer, and correlate genotype with phenotype on a cell by cell basis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA045919-07
Application #
2092051
Study Section
Pathology B Study Section (PTHB)
Project Start
1987-08-01
Project End
1996-08-31
Budget Start
1994-09-01
Budget End
1995-08-31
Support Year
7
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Pathology
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Albertson, D G; Ylstra, B; Segraves, R et al. (2000) Quantitative mapping of amplicon structure by array CGH identifies CYP24 as a candidate oncogene. Nat Genet 25:144-6
Pinkel, D; Segraves, R; Sudar, D et al. (1998) High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays. Nat Genet 20:207-11
Venkatachalam, S; Shi, Y P; Jones, S N et al. (1998) Retention of wild-type p53 in tumors from p53 heterozygous mice: reduction of p53 dosage can promote cancer formation. EMBO J 17:4657-67
Shi, Y P; Mohapatra, G; Miller, J et al. (1997) FISH probes for mouse chromosome identification. Genomics 45:42-7
Bain, G; Engel, I; Robanus Maandag, E C et al. (1997) E2A deficiency leads to abnormalities in alphabeta T-cell development and to rapid development of T-cell lymphomas. Mol Cell Biol 17:4782-91
Shi, Y P; Naik, P; Dietrich, W F et al. (1997) DNA copy number changes associated with characteristic LOH in islet cell carcinomas of transgenic mice. Genes Chromosomes Cancer 19:104-11
Balazs, M; Matsumura, K; Moore, D et al. (1995) Karyotypic heterogeneity and its relation to labeling index in interphase breast tumor cells. Cytometry 20:62-73
Younes, A; Zhao, S; Jendiroba, D et al. (1995) Decreased expression of the deleted in colorectal carcinoma gene in non-Hodgkin's lymphoma. Blood 85:2813-6
Sakamoto, M; Pinkel, D; Mascio, L et al. (1995) Semiautomated DNA probe mapping using digital imaging microscopy: II. System performance. Cytometry 19:60-9
Kallioniemi, A; Kallioniemi, O P; Piper, J et al. (1994) Detection and mapping of amplified DNA sequences in breast cancer by comparative genomic hybridization. Proc Natl Acad Sci U S A 91:2156-60

Showing the most recent 10 out of 32 publications