The University of Michigan has responded to the Director's Challenge with a proposal to utilize an integrated genomic and proteomic approach for DNA and protein analysis, for the molecular classification of tumors. A multi-disciplinary team with expertise in fields including Oncology, Pathology, Molecular Biology, Cancer Prevention, Clinical Trials, of national and international participating groups in place. The targeted tumors consist of a judicious choice of specific groups of colon, lung and ovarian cancers for which current classification schemes are uninformative with respect to the clinical behavior of the tumors. A detailed rationale for inclusion of different tumor types is provided which is based in part on common molecular features including the occurrence of mutations in the same pathogenetically relevant genes in the three tumor types. A special feature of this program is integration of gene expression analysis at both the RNA and protein levels. The program is organized into projects and cores. Each core will serve all projects thus substantially facilitating comparable processing of samples and integration of information across projects. Project one is aimed at devising a molecular classification on stages II and II colon tumors. Another project is aimed at devising a molecular based classification of serious carcinoma of the ovary. The last project is aimed at devising a molecular based classification for tumors that currently belong to stage I adenocarcinoma and squamous cell carcinoma of the ring. The first Core provides administrative support for the program. Another Core provides support for tissue procurement, pathologic evaluation of tissue specimens and tissue microdissection. The next Core is concerned with proteomic analysis of tumors. It is expected that approximately 1000 proteins will be identified in each tumor type and their abundance in individual tumors determined by quantitative two-dimensional electrophoresis. Another Core is concerned with tumor DNA microarray analysis. Initially, DNA microarrays will be utilized for expression profiling and for the analysis of mutant genes. In subsequent years DNA microarrays designed for genomic investigations, including analysis of deletions, amplifications, and methylation status, currently under development in a separate project and at no cost to this program will be utilized. Thus, for a large subset of genes that are expressed in the tumor types investigated, expression will be determined at both the RNA and protein levels. The last Core provides support with bioinformatics and statistical analysis. Internal and external advisory committees will assist in the operation of this program of research. Plans have been put into place for dissemination of data and for addressing issues of intellectual property.
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