? We have developed array CGH methodology for analysis of DNA copy number variations in the murine genome. Measurements of tumors from various cancer models have established the performance of the arrays, and the value of data they provide. Measurements employing an array that provides ~ 2 Mb resolution over the genome (~1500 BACs) found numerous DNA copy number polymorphisms among the standard mouse strains. The polymorphism may contribute to the strain-specific differences in phenotype and disease susceptibility that are exploited in cancer models. The rapid progress of the mouse genome project will allow us, in collaboration with the Vancouver British Columbia Genome Center, to produce an array containing a complete BAC tiling path of the mouse genome by the end of the current grant period. This array will contain about 30,000 clones. For the coming grant period we propose to use the whole genome tiling path array to comprehensively investigate DNA copy number polymorphisms among the mouse strains. This will include: ? ? 1. Validation of the performance of the tiling path array, including developing the informatics required to properly interpret the results. Validation will be accomplished through sequence analysis and hybridizations. In order to obtain specimens with a wide variety of copy number changes to test the arrays, and to collaborate with the MMHCC investigators, we will analyze ~1000 tumors from their various models. ? 2. Detection and mapping of copy number polymorphisms among mouse strains, and evaluation of their biological effects. We will use the tiling path array to map the polymorphisms by array CGH, characterize the genomic differences by sequence analysis, and carry out functional analysis as appropriate depending on the gene content of the regions. Comprehensive expression profiling will also be used to examine differences among the strains. New approaches for hybridization and analysis will be developed to extend the dynamic range of the expression measurements so we can obtain data from mRNAs expressed at very low abundances. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01CA084118-08
Application #
7057819
Study Section
Special Emphasis Panel (ZCA1-SRRB-U (J1))
Program Officer
Marks, Cheryl L
Project Start
1999-09-30
Project End
2009-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
8
Fiscal Year
2006
Total Cost
$429,926
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Ottolini, Barbara; Hornsby, Michael J; Abujaber, Razan et al. (2014) Evidence of convergent evolution in humans and macaques supports an adaptive role for copy number variation of the ?-defensin-2 gene. Genome Biol Evol 6:3025-38
Kumar, Prashant; Mukherjee, Malini; Johnson, Jacob P S et al. (2012) Cooperativity of Rb, Brca1, and p53 in malignant breast cancer evolution. PLoS Genet 8:e1003027
Bhattacharya, Aditi; Roy, Ritu; Snijders, Antoine M et al. (2011) Two distinct routes to oral cancer differing in genome instability and risk for cervical node metastasis. Clin Cancer Res 17:7024-34
Davari, Parastoo; Hebert, Jennifer L; Albertson, Donna G et al. (2010) Loss of Blm enhances basal cell carcinoma and rhabdomyosarcoma tumorigenesis in Ptch1+/- mice. Carcinogenesis 31:968-73
Halberg, Richard B; Waggoner, Jesse; Rasmussen, Kristen et al. (2009) Long-lived Min mice develop advanced intestinal cancers through a genetically conservative pathway. Cancer Res 69:5768-75
Tokuyasu, Taku A; Cotter, Philip D; Segraves, Richard et al. (2007) Detection of single clone deletions using array CGH: identification of submicroscopic deletions in the 22q11.2 deletion syndrome as a model system. Am J Med Genet A 143A:925-32
Hamilton, G; Brown, N; Oseroff, V et al. (2006) A large field CCD system for quantitative imaging of microarrays. Nucleic Acids Res 34:e58
Iglesias, Alejandro; Rauen, Katherine A; Albertson, Donna G et al. (2006) Duplication of distal 20q: clinical, cytogenetic and array CGH. Characterization of a new case. Clin Dysmorphol 15:19-23
Glass, Ian A; Rauen, Katherine A; Chen, Emily et al. (2006) Ring chromosome 15: characterization by array CGH. Hum Genet 118:611-7
Albertson, Donna G (2006) Gene amplification in cancer. Trends Genet 22:447-55

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