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

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

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

Interstitial Cells of Cajal

Innervated network of KIT+ cells, associated with Auerbach’s plexus

“Pacemaker” function coordinates peristalsis

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GIST
Spindle cell Epithelioid

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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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-

GIST: Clonal Evolution of Cytogenetic Abnormalities

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)

Molecular Targets in GIST cells


	Jonathan A. Fletcher, MD
	Dept of Pathology, Brigham & Women’s Hospital; Depts of Pediatric and Adult Oncology, Dana-Farber Cancer Institute; Boston, MA


	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


	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


	Innervated network of KIT+ cells, associated with Auerbach’s plexus
	“Pacemaker” function coordinates peristalsis



	Familial GIST syndromes: germline KIT gain-of-function mutations and ICC hyperplasia
	KIT mutations in incidental GISTS
	KIT mutations antedate cytogenetic aberrations


	“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-


	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)