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Our lab is focused on the identification of cancer-related genes using high throughput, whole genome approaches to the analysis of human tumors and their counterparts from murine models. This work encompasses three major projects.
First, we have implemented array comparative hybridization as our primary means of tumor analysis. Previous strategies to identify oncogenes and tumor suppressor genes have been limited by absence of the complete human genome sequence and methods for rapid, genome-wide analysis. Array comparative genomic hybridization (aCGH) measures relative copy number by competitive differential hybridization of labeled genomic DNA to DNA microarrays. The use of densely-spaced, sequence-mapped BACs for aCGH provides a high-throughput whole genome approach to identifying genes amplified or deleted in cancers. Thus aCGH circumvents many previous limitations in the identification oncogenes and tumor suppressor genes. We have constructed CGH arrays of ~5000 human BAC clones with an average resolution of 1 Mb.
We have developed several software packages devoted to array CGH analysis and data visualization that are downloadable as a part of a larger on-line resource for array CGH development and analysis. The CGH Browser experiment viewer plots clone ratios vs. genomic location by chromosome. Unlike typical methods for generating these plots, the CGH Browser can handle multiple experiments simultaneously (including dye swap analysis), allow users to annotate experiment results, export results to files or databases, and ultimately link mapped clones to several on-line line genome feature databases (e.g. NCBI MapViewer and Ensembl). The CGH Circle Viewer is another downloadable visualization tool that efficiently displays an entire CGH experiment in a single circular format and allows overlay of data from multiple experiments, identifying common gains and losses. In addition to these CGH analysis tools, we have developed novel means of visually integrating mapped genome features and their associated annotations with aCGH data in the circular format. One can effectively link an aberrant region of the genome seen in an aCGH experiment to features on a physical map (e.g. Unigene genes and STSs).
Secondly, we have implemented Affymetrix-based expression profiling as an adjunct to array CGH. We will use this combined approach to identify patterns of chromosomal gains and losses in array CGH data, then combine these data with expression patterns that compare tumor to normal adjacent tissue. This comparison will allow us to define up and down regulated genes in these regions, a means of prioritizing loci for mutation screening. It will also identify genes that are differentially regulated in a panel of tumors compared to normal. These data will assist in the identification of genes that may be dysregulated by epigenetic mechanisms.
Finally, we have developed a mouse model of BRCA1 tumorigenesis that we will subject to genomic analysis. This mouse has a hypomorphic Brca1 allele that is deleted for the C-terminal BRCT domain. It also should be a useful model to evaluate premalignant changes associated with BRCA1 loss in mammary epithelium. We will use array CGH and expression profiling to evaluate the associated genetic changes and will use the versatility of the murine system to evaluate the effects of estrogen on this process.
In addition to our genomics effort, we continue to work on optimizing the use of genetic susceptibility testing with translational studies of BRCA1 and BRCA2 mutation frequency, penetrance, associated modifier genes, and the efficacy of preventative interventions. One difficulty in translating findings from large collaborative research studies into a clinical setting is concerns over differences in penetrance in families ascertained for research studies and those ascertained in a risk evaluation clinic. In order to identify modifier loci, we are integrating a genomics and candidate gene approach and have recently published evidence that there is a locus on distal chromosome 5 that contains a novel modifier gene. We also have completed work describing the profile and BRCA1 and BRCA2 mutation frequency of patients seen in a clinical program and the mutation frequency in those patients with multiple primary cancers. Finally, we have completed a statistical analysis of breast and ovarian cancer penetrance in a clinic population and in addition to demonstrating that this estimate is close to that obtained from research cohorts, we have identified several unrecognized cancer risks including stomach and fallopian tube cancers.
Background
Dr. Weber received her B.S. in Chemistry and her M.D. from the University of Washington, Seattle, WA. She received her clinical training in Internal Medicine at Yale University and in Medical Oncology at the Dana-Farber Cancer Institute, Boston, MA. She received additional training in molecular biology at Harvard University and the University of Michigan, where she received her first faculty appointment in 1990. She is Board Certified in Internal Medicine and Medical Oncology and was elected to the American Society of Clinical Investigation in 1997.
Dr. Weber is an international leader in the field of breast cancer genetics. She is a Professor of Medicine and Genetics at the University of Pennsylvania. She developed the Breast Cancer Program at the Abramson Cancer Center at the University of Pennsylvania in 1995 and has served as the director since that time. In this capacity, she implemented and directs the Breast Cancer Risk Evaluation Program, a clinical service designed to provide comprehensive risk assessment and counseling services to women with a strong family history of breast cancer. This program was among the first of its kind in the world and has served as a model for developing programs throughout the US.
Dr. Weber is active nationally and internationally with several key groups in research policy and education. She chairs the NCI Genetics Working Group, assembled by the NCI Director Richard Klausner to advise him in this area, and was appointed to the NCI Board of Scientific Advisors in 1997. She has advised the American Cancer Society, American Society of Clinical Oncology (ASCO) and the American Medical Association in the development of the materials to educate American physicians on cancer susceptibility testing. She is the Chair of the Steering Committee for the NCI-sponsored Cancer Genetics Network, a consortium of eight cancer genetics centers selected by competitive application, and she is a member of the Steering Committee of the International Breast Cancer Linkage Consortium. |
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