THIS IS A SHANNON AWARD PROVIDING PARTIAL SUPPORT FOR THE RESEARCH PROJECTS THAT FALL SHORT OF THE ASSIGNED INSTITUTE'S FUNDING RANGE BUT ARE IN THE MARGIN OF EXCELLENCE. THE SHANNON AWARD IS INTENDED TO PROVIDE SUPPORT TO TEST THE FEASIBILITY OF THE APPROACH; DEVELOP FURTHER TESTS AND REFINE RESEARCH TECHNIQUES; PERFORM SECONDARY ANALYSIS OR AVAILABLE DATA SETS; OR CONDUCT DISCRETE PROJECTS THAT CAN DEMONSTRATE THE PI'S RESEARCH CAPABILITIES OR LEND ADDITIONAL WEIGHT TO AN ALREADY MERITORIOUS APPLICATION. THE ABSTRACT BELOW IS TAKEN FROM THE ORIGINAL DOCUMENT SUBMITTED BY THE PRINCIPAL INVESTIGATOR. DESCRIPTION: (adapted from the investigator's abstract) Recent advances have uncovered many of the somatic mutations which characterize multistep tumor progression. In contrast, relatively less is known about how tumors grow. When does tumorigenesis initiate? How fast do tumors expand? Do tumors grow constantly or in discrete stages? Such questions are difficult to answer since serial observations of human tumors are rare. However, for most cancers, how fast and to what extent they invade or metastasize determines their lethality. They propose to employ the phylogenetic techniques used to study human evolution and migration on the analogous problem of tumor progression and expansion. The topographical distributions and microsatellite (MS alterations acquired in colorectal cancers with mutator phenotypes provide clues to past patterns of tumor progression. MS loci are ideal """"""""molecular"""""""" tumor clocks since they are neutral and continue to accumulate changes during tumor progression. Preliminary studies of human hereditary nonpolyposis colorectal cancers reveal MS allelic diversity in older tumor regions but less diversity in younger or invasive tumor regions. Since diversity equals antiquity in population genetics, these findings are consistent with the """"""""out of adenoma"""""""" hypothesis. Tissue culture or xenograft studies with mutator cell lines provide experimental opportunities to validate possible mechanisms responsible for the human tumor patterns. These studies will test the hypothesis that somatic MS alterations reveal past growth patterns and the number of cell divisions between tumor initiation and clinical presentation.
