1	Molecular Biology of GIST Jonathan A. Fletcher, MD Dept of Pathology, Brigham & Women’s Hospital; Depts of Pediatric and Adult Oncology, Dana-Farber Cancer Institute; Boston, MA
2	I. ICC & KIT Become the Focus GIST progenitor cell might be of the Interstitial cell of Cajal (ICC) lineage. Atayde-Perez & Kozakewich AJSP 1993: “The tumor cells in our patient and Cajal interstitial cells share certain common ultrastructural features…. support an origin from the interstitial cells of Cajal” ICC proliferation, as required for ICC to populate the GI tract, depends on expression of the KIT receptor tyrosine kinase
3	KIT (CD117) KIT gene encodes a 145 kD transmembrane receptor tyrosine kinase Belongs to a family that includes receptors for PDGF, M-CSF and flt3 ligand Important in normal hematopoiesis, melanogenesis, gametogenesis, development of interstitial cells of Cajal, and mast cell growth/differentiation Activation stimulates cell growth & survival, e.g. through the MAPK and PI3K/AKT/mTOR signaling cascades
4	Interstitial Cells of Cajal Innervated network of KIT+ cells, associated with Auerbach’s plexus “Pacemaker” function coordinates peristalsis
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9	GIST Spindle cell Epithelioid
10	II. Evidence for KIT Activation as a Crucial Oncogenic Mechanism in Most GISTs Familial GIST syndromes: germline KIT gain-of-function mutations and ICC hyperplasia KIT mutations in incidental GISTS KIT mutations antedate cytogenetic aberrations
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12	GIST Cytogenetics - Mechanisms of Neoplastic Progression “Benign” and “Malignant” GISTs are on a genetic continuum, progression to malignancy being accompanied by acquisition of characteristic cytogenetic deletions: -14, -22, 1p-, 9p-, 11p-
13	GIST: Clonal Evolution of Cytogenetic Abnormalities
14	Summary Evidence for KIT activation as a central oncogenic mechanism in most GISTs Developmental Biology (KIT role in ICC) Histopathology (GISTs arise from ICC lineage; KIT is expressed strongly and diffusely in most GISTs) Cancer Biology (KIT gain-of-function mutations are found in most GISTs, and antedate other known characteristic mutations) Cancer Genetics (initiating role of KIT gain-of-function mutation in familial GIST syndromes)
15	Molecular Targets in GIST cells