Small-bowel tumors: molecular mechanisms and targeted therapy

Abstract

Introduction The small bowel (jejunum and ileum) comprises 90% of the surface area of the gastrointestinal tract (GIT), but tumors of the small bowel constitute a very small proportion of GIT tumors. Theories to explain the low incidence of small-intestinal tumors include high cellular turnover and apoptosis, and low bacterial counts in small-intestinal effluent. Several histological subtypes of small-bowel tumors exist: namely, the rare type of sarcoma known as gastrointestinal stromal tumor (GIST), adenocarcinoma of the small bowel, tumors arising from Peutz–Jeghers hamartomas, and carcinoid tumors. Despite the low incidence of small-bowel tumors, the molecular mechanisms have been well established in some tumors, and specific therapeutic targets have been the hallmark of targeted cancer therapy in GIST. This chapter highlights the molecular mechanisms of GIST, Peutz–Jeghers malignancies, and adenocarcinoma, and discusses existing and potential therapeutic targets. GIST Background cytogenetic and LOH data that led to cancer gene identiication This uncommon tumor has received much attention as it has formed the foundation for targeted cancer treatment. The tumor is thought to arise fromthe intestinal cells of Cajal which undergo malignant transformation following a mutation in the KIT gene. Gastric GISTs commonly have mutations of plateletderived growth factorA(PDGFA).herole of KITmutations in GIST was irst described byHirota and colleagues,who used the mast-cell analogy, where lack of KIT resulted in mast-cell deficiency and activation resulted in mast-cell neoplasia, to demonstrate the role of constitutional activation of KIT in GIST (1). he interstitial cells of Cajal (the cell of origin in GIST) are usually positive for KIT and can diferentiate to smooth muscle cells if normal KIT signaling is disrupted. KIT is a type III receptor tyrosine kinase which is encoded by the protooncogene c-kit . Activation mutations of the c-kit gene lead to ligand-independent constitutional activation of KIT and phosphorylation of the receptor tyrosine kinases, thereby activating downstream efectors (2–4). his perpetual activation of the receptor results in cellular proliferation and a decrease in apoptosis. Mutually exclusive mutations in Kit or PDGFRA are observed in 80%% of GIST (2). Mutations in diferent regions of the KIT gene occur in sporadic GIST with consequent influences on the biologic behavior and prognosis, as will be detailed later. he exon mutations in order of frequency are exons 11, 9, 13, and 17.