Program Leader John Witte, PhD Program Co-Leader Allan Balmain, PhD

The Cancer Genetics Program, comprising more than 30 members, is dedicated to the elucidation of the genetics of tumor susceptibility, tumorigenesis, and progression, and to the utilization of this information clinically to improve cancer management. The program encourages the application of advanced genomic and genetic analysis tools to identification of abnormalities that contribute to cancer genesis and progression in humans and in animal models.

The program has identified four broad research themes:

Advanced Analytical Technologies
This theme focuses on development of advanced techniques for analysis of genomic and genetic abnormalities, techniques that include expression and CGH arrays; gene expression analysis in mice and humans; analysis of structural chromosome rearrangements; and high-throughput genotyping. In addition, Cancer Center investigators collaborate with local bioengineering programs at UCSF, UC-Berkeley, Lawrence Berkeley National Laboratory, and Lawrence Livermore National Laboratory to bring advanced analytical capabilities to Cancer Center investigators.

Familial Cancer Genetics
The goal of this theme is to identify genetic events that influence susceptibility to cancer. This is accomplished by identifying genetic loci that are associated with susceptibility to cancer in murine tumors and that confer substantially increased susceptibility when inherited together. Polymorphisms at syntenic loci in humans are then tested for association with altered risk of developing cancer. Human association studies will incorporate information about regions of recurrent genome copy number abnormality in human tumors, since murine studies have demonstrated that genes that confer increased susceptibility/resistance are often selected for/against during tumor formation. This requires:

• development of close relationships with national and international consortia to identify genes associated with genetic risk;

• integration of information on locations of human and mouse genome and gene expression abnormalities, mouse susceptibility loci, and human and mouse SNP content;

• development of low-cost, high-throughput genotyping capabilities for mouse and human;

• analysis of genome copy number abnormalities in tumors from patients from high-risk cohorts; and

• development of informed consent procedures for genetic/genomic studies.

Genomic Research
The program aims to apply efficient technologies for analysis of gene copy number, gene expression, methylation status, and the human genome sequence to identify genes that contribute to cancer genesis or progression. These efforts will likely increase understanding of the biological events that enable cancer progression, leading directly to improved strategies for early detection, prognostication, prediction of response to therapy, and new targets for therapeutic intervention. Employed in this effort are powerful computational techniques for gene discovery and functional assessment; analysis of human tumors and use of these data to generate a comprehensive database of genomic aberrations present in human tumors; and increased interaction with biologically oriented members of other programs to facilitate functional assessment of newly discovered cancer genes.

Bioinformatics
This theme emphasizes the development of informatics techniques to manage, integrate, and interpret the vast amounts of genetic and biological information from modern genomic, genetic, and biological research. Among other components, these techniques require:

• Significant basic research in statistical, machine learning, visualization, and other approaches to leverage the biological data being collected.

• Development of web-oriented information exchange capabilities that enable investigators to contribute to and access communal databases.

• Development of standard data dictionaries and data exchange protocols.