The importance of molecular biology in development, prognosis, treatment and resistance to targeted therapy in gastroint
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REVIEW
The importance of molecular biology in development, prognosis, treatment and resistance to targeted therapy in gastrointestinal stromal tumors Alessandro Comandone • Elisa Berno • Simona Chiadò Cutin • Antonella Boglione
Received: 24 April 2008 / Accepted: 18 May 2008 / Published online: 26 June 2008 © Springer-Verlag 2008
Abstract Gastrointestinal stromal tumors (GISTs) are the commonest mesenchymal tumors of the gastroenteric tract, and are generally believed to originate from the neoplastic transformation of the interstitial cells of Cajal, the pacemaker structures of the stomach and intestine. Exon and genetic mutations (point/deletions) are fundamental for the development of GISTs: the constitutional characteristic of this neoplasm is the presence of the cell surface Kit receptor. Kit is the product of the proto-oncogene cKit, situated in chromosome 4. Ninety-eight percent of GISTs express mutated isoforms of Kit or of PDGFRA (Platelet growth factor receptor α). Kit mutation is the basic condition for autophosphorylation of tyrosine kinase residues in proteins. Autophosphorylation initiates pathogenetic processes in Cajal cells, toward a neoplastic transformation.
Imatinib mesilate and, more recently, sunitinib are tyrosine kinase inhibitors, specific antagonists for Kit and PDGFRA, with good activity against GISTs. Most molecular and clinical data currently available concern imatinib. Exon mutations are strategic as prognostic and as predictive factors. In recent years, much evidence suggests that survival, response to therapy and resistance to imatinib are related to different mutations. In the near future, GIST patients will receive treatment differentiated by expressed Kit and PDGFRA mutations, thus truly individualized therapy.
Keywords Gastrointestinal stromal tumors • Kit and PDGFRA mutations • Clinical response • Resistance to tyrosine kinase inhibitors
Introduction
A. Comandone (Y) Division of Medical Oncology, Gradenigo Hospital, C.so Regina Margherita 8, 10153, Torino, Italy e-mail: [email protected] E. Berno • S. Chiadò Cutin • A. Boglione Oncology Unit, Ospedale Gradenigo, Turin, Italy and Piedmont Group for Sarcomas
Although relatively rare, GISTs are the commonest mesenchymal tumors of the gastrointestinal tract. Their incidence is calculated at almost 2/100,000/year, and the prevalence in the Southern Sweden registry is about 125/100,000 [1–6]. GISTs can arise not only from the gastrointestinal tract, but also in the omentum, mesentery and at extra-intestinal sites. They are assumed to be the malignant transformation of the intestinal pacemaker cells of Cajal [5], and are positive for CD34 in about 60% of cases [7]. Cajal cells have either smooth muscle or neural differentiation, but in GISTs only one feature prevails [8, 9, 10]. Such neoplasms in the gastrointestinal tract are commonest in the stomach [40%–70%] and small intestine (20%–40%). Only 5% are found in the colon-rectum, and the same percentage in the esophagus; fewer than 1% are extra-intestinal [11].
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