Somatic pharmacogenomics of gastrointestinal stromal tumor

Abstract

Gastrointestinal stromal tumors (GISTs) are rare entities, which, however, represent the most common mesenchymal tumor of the gastrointestinal tract. The discovery of gain of function mutations on KIT and PDGFRA receptor genes led to a deep revolution in the knowledge of this tumor. This paved the way to the introduction of imatinib and other tyrosinekinase inhibitors (TKIs), which terrifically revolutionized the prognosis of GIST patients. Currently, it is well established that tumor mutational status is the main player in clinical outcome; however, with the research advances, it has been slowly understood that GIST landscape is more complex than expected and the TKIs available are not effective for all the GIST subtypes. For this reason, in the era of tailored/personalized medicine, each GIST patient should be considered individually and genetic consult should be the first step to take in consideration in the therapeutic decision making process.

“Pharmacogenetics of Cancer” - Cancer Drug Resistance special issue

“…After the identification of gain-of-function mutations in KIT and PDGFRA receptor genes that opened the way to the treatment with inhibitors of c-KIT and platelet-derived growth factor receptor A (PDGFRA) tyrosine kinase receptors (e.g., imatinib and newer analogs) in succinate dehydrogenase (SDH) competent GIST, it is today known that mutations in other molecules, such as BRAF or RAS , or mutations in SDH subunits that lead to SDH deficient GISTs represent different subtypes with specific features affecting prognosis and clinical outcome. The review of Ravegnini et al [ 26 ] focuses on tumor alterations in GISTs in relation to response to the available drugs. A mention of GIST germline DNA alterations and their possible role in drug efficacy/resistance is also provided, although this matter is still the subject of debate.…”