Program Profile

Membership:
23 members
20 departments
   6 schools

Project Funding as of 9/2006 (direct costs):

Peer-reviewed	$13.5 M	39
NCI	$2.2 M	8
NIH	$10.5 M	24
ACS	$0.2 M	1
NSF	$ 0.6 M	5
Other P-R	$0.03M	1
Non peer-reviewed	$0.7M	6
Total	$7.6M	45

Three strongly interacting facets support the central theme of the Cancer Genetics Program at the UWCCC: to understand the relationships between cancer phenotype and genotype. The specific goals to be addressed within these three synergistic facets of Cancer Genetics are:

Mammalian and human genetics

• Murine models for human cancer and pathway/network analysis
• Modifier loci for resistance/susceptibility to particular neoplasms
• Genetic/genomic stability factors
• Cytogenetics of cancer
• The role of oxidative stress in age-associated carcinogenesis
• Connections between murine models and human populations

Genomics and genetically indexed transcriptomics/proteomics/metabolomics

• Molecular mapping of the murine and human genomes in cancer
• Genetically-defined or age-stratified differential proteomic and metabolomic analysis of tumors and body fluids, from murine genetic models for human cancer
• Structural analysis of proteins guided by mutational validation of function

Statistical genetics and informatics

• Positional cloning of loci with only quantitative phenotypic effects
• Pattern analysis of tissue interactions in genetic chimeras and mosaics
• Deconvolution of array data and complex tandem mass spectra
• The statistics of population association data

Significant Recent Discoveries

• Combination of genomic and proteomic analysis of molecular interactions to deduce at least five distinct signaling steps involved in the action of the aryl hydrocarbon receptor. (PLoS Biol 2:E65, 2004)
• Creation of a rat kindred mutated in the gatekeeper gene for colon cancer, Apc, showing a predisposition for colonic neoplasia. (Cold Spring Harbor December 2005 Rat Genome Meeting)
• Use of new methods of spatial statistics with biological analysis of chimeric Min mice to establish that early familial adenomas are commonly polyclonal in structure. (Proc Natl Acad Sci USA 102:6960-5, 2005, A PNAS Cover citation)
• Analysis of the portion of the transcriptome differentially expressed in white adipose tissue under conditions of longterm caloric restriction, and discovery that the cancer-related gene Hif-1α is among the 104 genes down-regulated by caloric restriction. (J Nutr 136:343-52, 2006)
• Development of a revolutionary capacity called Optical Mapping to detect aberrations in cancer genomes from very small numbers of cells. (Science, submitted 2006)
• Development of the capacity to detect single cleaved DNA molecules on surfaces and demonstrated surface invasive cleavage for the multiplex analysis of genetic markers, pointing the way toward sensitive and comprehensive analysis of variation in whole genomes. (Anal Chem 77:6594-600, 2005 and Anal Chem 77:2400-5, 2005)
• Analysis of RecQ helicases involved in genomic stability has shown that, among the human helicases, the Bloom’s Syndrome molecule specifically carries the capacity to unwind double Holliday junctions. (EMBO J 24:2679-87, 2005)
• Development of several modes of differential proteomic analysis by mass spectrometry, including the analysis of the extent of phosphorylation at individual sites in multiphosphorylated proteins. (J Am Soc Mass Spectrom 15:647-53, 2004)
• Statistical analysis of microarray data, defining the conditions that maximize the advantages of pooling mRNA samples. (J Comput Biol 8:37-52, 2001. [recognized as a ‘highly cited article’ by ‘Web of Science’; Google Scholar search shows 280 citations] and Biostatistics 4:465-477, 2003)
• Invention of maskless array technology and development of the capacity for creating thousands of gene sequences per day be assembly of fragments eluted from chips. (Nucleic Acids Res 32:5011-8, 2004).

Recent Cancer Genetics Publications