The detailed cytogenetic analyses of human tumors and cancer tissues, in particular, have revealed the presence of structural chromosome abnormalities in most of cases. The underlying changes are often specific for the type of tumor or cancer and the cells' altered phenotype. Furthermore, investigators could demonstrate a correlation between the type or extent of chromosome changes, disease progression, and outcome. However, present laboratory techniques for the screening for structural abnormalities are very limited with respect to the detection of small, 'cryptic' translocations. For example, Giemsa (G)-banding of metaphase chromosomes or the fluorescence in situ hybridization (FISH)-based techniques of whole chromosome painting (WCP) and Spectral Karyotyping (SKY) analysis typically miss translocations that involve segments of less than 10 megabasepairs (Mbp), i.e., about the size of a chromosome band. We postulate that small cryptic translocations exist undetected in the genomes of individuals with a normal phenotype or diseases such as mental retardation, impaired fertility, precancerous lesions, or early stage tumors. Knowledge about structural alterations and chromosomal imbalances might help clinicians make more accurate predictions regarding the onset and course of a disease. This R21 project will investigate the feasibility to rapidly and inexpensively screen the human genome for the presence of occult cryptic translocations (OCTs). Specifically, we will develop and test FISH assays using collections of validated chromosome-specific bacterial artificial chromosomes (BACs) for the detection of OCTs in human cancer cells. With BAC probes spaced on average 0.9 Mbp apart and covering the entire euchromatic part of the human genome, we expect our 'BAC-FISH' assay to lead to greatly increased sensitivity compared to WCP or banding tests. Our innovative assay for sensitive genome-wide screening for translocations will be developed with cancer cell lines for which limited information about structural abnormalities is available. At the end of this project, we will be well positioned to conduct a larger study of the frequency of OCTs in the normal population as well as tumor cells and to offer BAC-FISH screening service and reagents to research and clinical laboratories for collaborative studies. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA123370-01A1
Application #
7290761
Study Section
Special Emphasis Panel (ZCA1-SRRB-C (M1))
Program Officer
Tricoli, James
Project Start
2007-09-01
Project End
2009-08-31
Budget Start
2007-09-01
Budget End
2008-08-31
Support Year
1
Fiscal Year
2007
Total Cost
$177,894
Indirect Cost
Name
Lawrence Berkeley National Laboratory
Department
Genetics
Type
Organized Research Units
DUNS #
078576738
City
Berkeley
State
CA
Country
United States
Zip Code
94720
O'Brien, Benjamin; Zeng, Hui; Polyzos, Aris A et al. (2013) Bioinformatics tools allow targeted selection of chromosome enumeration probes and aneuploidy detection. J Histochem Cytochem 61:134-47
Zeng, Hui; Weier, Jingly F; Wang, Mei et al. (2012) Bioinformatic Tools Identify Chromosome-Specific DNA Probes and Facilitate Risk Assessment by Detecting Aneusomies in Extra-embryonic Tissues. Curr Genomics 13:438-45
Klymenko, Sergiy V; Smida, Jan; Atkinson, Michael J et al. (2011) Allelic imbalances in radiation-associated acute myeloid leukemia. Genes (Basel) 2:384-93
Weier, Heinz-Ulrich G; Ito, Yuko; Kwan, Johnson et al. (2011) Delineating chromosomal breakpoints in radiation-induced papillary thyroid cancer. Genes (Basel) 2:397-419
O'Brien, Benjamin; Jossart, Gregg H; Ito, Yuko et al. (2010) 'Chromosomal Rainbows' Detect Oncogenic Rearrangements of Signaling Molecules in Thyroid Tumors. Open Cell Signal J 2:13-22
Bednarz, Natalia; Eltze, Elke; Semjonow, Axel et al. (2010) BRCA1 loss preexisting in small subpopulations of prostate cancer is associated with advanced disease and metastatic spread to lymph nodes and peripheral blood. Clin Cancer Res 16:3340-8
Weier, H-U G; Kwan, J; Lu, C-M et al. (2009) Kinase expression and chromosomal rearrangements in papillary thyroid cancer tissues: investigations at the molecular and microscopic levels. J Physiol Pharmacol 60 Suppl 4:47-55
Weier, Heinz-Ulrich G; Greulich-Bode, Karin M; Wu, Jenny et al. (2009) Delineating Rearrangements in Single Yeast Artificial Chromosomes by Quantitative DNA Fiber Mapping. Open Genomics J 2:15-23
Lu, Chun-Mei; Kwan, Johnson; Weier, Jingly F et al. (2009) Rapid mapping of chromosomal breakpoints: from blood to BAC in 20 days. Folia Histochem Cytobiol 47:367-75
Kwan, Johnson; Baumgartner, Adolf; Lu, Chun-Mei et al. (2009) BAC-FISH assays delineate complex chromosomal rearrangements in a case of post-Chernobyl childhood thyroid cancer. Folia Histochem Cytobiol 47:135-42

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