Question ID: WS-113
Submitted by: Steven Smith
August 15, 2011
Can a Map of the Evolving Frangiome be Produced? Cancer is a form of accelerated evolution. As such alterations in genome structure, gene expression and epigenetic change are all potentiated by the current state of the cell and by its environment as a source of mutagenesis and selective pressure. For example gene rearrangements can be potentiated by chromatin juxtapositions in a given cell type. The TMPRSS2:ERG fusion for example is not likely to occur in a breast cancer because the juxtaposition of the to two portions of chromosome 21 involved in the fusion appears to be a specific response of the differentiated prostate cell to androgen. It follows that, at each stage of tumor progression alterations in chromosome number, regional copy number and chromosome aberration, will potentiate a different set of future alterations, which will be under the influence of the tumor micro and macro-environment. Given these facts it may be possible to develop methods for identifying weak spots in chromosomes elicited by these progression-associated alterations. This is best thought of in terms of what I call genome frangibility: the tendency of a given genome state exhibit a specific set of sites that are easily broken by genomic stresses. This requires not only the mapping of what is best termed the frangiome of normal cells compared to cancer cells, but also comparing the frangiome of circulating tumor cells and dormant cancer cells with that of metastatic cells. By mapping the available weak points and juxtapositions in the genomes of each of these tumor cell types we will begin to be able to stage cancer more accurately and we will be able to more accurately design therapies to fit the different stages of the disease. Applicable methods in this search should include methods like sequence level mapping of chromosome breakpoints, Chromosome Conformation Capture and by emerging methods for detecting cell type specific and cancer specific non-B DNA structure.
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