Genetically engineered mice (GEM) develop novel disease patterns that create new challenges for comparative pathology that could not have been envisioned. The fundamental genetic alterations introduced into GEM have unique effects on the microscopic structure of tumors. This chapter presents an accurate picture of how specific abnormalities of molecular function influence tumor morphology. Gene-specific tumor phenotypes can now be recognized. Most important, the microscopic patterns of human and GEM cancers are nearly identical when carrying the same genetic aberrations. Currently available models provide the basis for organizing these newer observations and assessing their significance, their ramifications, their internal contradictions, and their applicability to existing scientific paradigms. The chapter is the first step in an iterative process that seeks to summarize, organize, and assess the new functional-structural knowledge base and how it applies to naturally occurring cases in other animals and humans. The molecular revolution and the sequencing of genomes have brought tremendous new insights into disease mechanisms but have had relatively little impact on the discipline of anatomic pathology. Pathologists give credence to molecular pathology, but this new knowledge has thus far not resulted in fundamental changes in the organ- and cell-centric approach to pathology. Although the organ systems approach is not necessarily inaccurate or incorrect, the time has come to assess the structure of neoplastic disease from the perspective of the genes and their products.
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