Gastrointestinal Stromal Tumours

Origin and Molecular Oncology

Christopher L. Corless; Christine M. Barnett; Michael C. Heinrich

In This Article

Abstract and Introduction


Gastrointestinal stromal tumours (GISTs) are a paradigm for the development of personalized treatment for cancer patients. The nearly simultaneous discovery of a biomarker that is reflective of their origin and the presence of gain-of-function kinase mutations in these tumours set the stage for more accurate diagnosis and the development of kinase inhibitor therapy. Subsequent studies of genotype and phenotype have led to a molecular classification of GIST and to treatment optimization on the basis of molecular subtype. The study of drug-resistant tumours has advanced our understanding of kinase biology, enabling the development of novel kinase inhibitors. Further improvements in GIST treatment may require targeting GIST stem cell populations and/or additional genomic events.


Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal tumour of the gastrointestinal tract. Studies across the world show remarkably consistent annual incidences of 11 to 19.6 per million population,[1–4] corresponding to between 3,300 and 6,000 new cases per year in the United States. Following surgical resection, GISTs often recur locally, spread diffusely throughout the serosal surfaces of the abdomen and/or metastasize to the liver. Advanced disease is associated with metastases to distant sites, including to the lung and bone. Prior to the advent of targeted therapies, the prognosis for advanced GISTs was poor owing to their inherent resistance to both chemotherapy and radiation therapy.[5]

During the past decade, GISTs have served as an important model in the emerging field of molecularly targeted therapies for solid tumours. The nearly simultaneous discovery of oncogenic kinase mutations in GISTs and the introduction of kinase inhibitor therapies has led to a rapid evolution in our understanding of these tumours and the biology that defines them.

This Review provides an overview of the exciting developments that have resulted from studies of the molecular pathology, pharmacology and oncology of GISTs. An emphasis is placed on the oncogenic mutations that lead to GIST development, the relationship between these mutations and responses to new classes of targeted therapeutics, and the insights into GIST biology that have been gained from molecular studies.