Getting the gist: what is the importance of molecular genetics in gastro-intestinal stromal tumours (GIST).

Gastrointestinal Stromal Tumour (GIST) is a rare disease but the most common mesenchymal neoplasm of the gastrointestinal tract. It has an incidence of 14.5-15 per million people. GIST tumor cells originate from the precursors of interstitial cells of Cajal (ICC), and are Kit/CD117 and CD34 positive. The key prognostic factors indicative of GIST metastasis, disease advancement and recurrence are the tumour size and the mitotic index. The anatomical site may also be informative for risk stratification. Despite existing differences in GIST clinicopathology, 75-80% of these tumors have an oncogenic mutation in the KIT (v-kit Hardy-Zuckerman feline sarcoma viral oncogene homolog) or PDGFRa (platelet-derived growth factor receptor, alpha polypeptide) genes. These gain of function mutations have been linked to GIST pathogenesis. Indeed both genes, which map to chromosome 4q12, belong to the type III tyrosine kinase family and encode highly homologous transmembrane glycoproteins. Neurofibromatosis 1 (NF1) patients have an increased risk of developing GISTs, although they will rarely have any KIT or PDGFRa mutations. The treatment of GIST patients has drastically changed since the introduction of tyrosine kinase inhibitors (TKI), such as Imatinib mesylate, which targets KIT and PDGFRa.