Our mathemafical/computafional Preliminary Studies emphasize the analysis of experimental data collected by our mulfidisciplinary team at Center of Cancer Systems Biology in conjuncfion with human data from the literature, to construct a predicfive model of dynamic steps in carcinogenesis ? Initiation consists of one or more comparatively rapid genomic or epigenetic alterations;the alterations produce cell clones that may become dysplasfic or hyperplastic and are at risk for being transformed. ? Promotion, according to one common view, involves the proliferation of initiated, and thus premalignant, cells. Promofion may take many years and the cell lineages may incur addifional alterations. ? (Malignant) transformation is a further genomic or epigenefic alterafion in an inifiated/promoted lineage. Somefimes, transformation is considered to be one point mutafion in a key gene, but other models consider larger scale DNA changes (e.g. deletions, duplicafions, translocafions and inversions, aneuploidy, or horizontal transfer) and/or consider mulfiple alterafions instead of just one alterafion. ? Progression occurs as a malignant cell lineage evolves in interacfion with its microenvironment, often becoming increasingly malignant and invasive. Genomic instability is a common feature. Many computational models implement all or part of this fimeline, often with addifional steps (reviewed, e.g., in [Cox &Huber 2007;Little et al. 2008a]). One basic implementafion is the classic two-stage clonal expansion (TSCE) model [Moolgavkar &Luebeck 2003], which emphasizes probabilisfic promotion. """"""""Two-stage"""""""" refers to initiation to pre-malignancy (stage 1) and transformation to malignancy (stage 2).
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