Rectal gastrointestinal stromal tumors associated with a novel germline KIT mutation

Somatic, activating mutations of KIT or PDGFRA are early oncogenic events in the majority of sporadic gastrointestinal stromal tumors (GISTs). Also a number of families with GISTs have been described in recent years. The familial GIST syndrome is a rare autosomal dominant disorder with high penetrance and diverse manifestations associated mostly with germline KIT mutations. In this report, we show a novel germline mutation in the juxtamembrane domain of KIT, identified in 2 brothers, both presenting with recurrent, high risk/malignant rectal GISTs. The KIT p.Q575_P577delinsH mutation was found in tumor samples as well as in peripheral blood leukocytes from both patients, proving that the mutation was indeed inherited. Besides rectal GISTs, no other features characteristic for the familial GIST syndrome was observed in either brother or any of their first-degree relatives. The patients were treated with imatinib, achieving either long-term partial response or stable disease. This observation confirms that imatinib can be successfully used in familial GISTs, as it is used in the sporadic advanced tumors, and that tumors bearing a KIT p.Q575_P577delinsH mutation are responsive to imatinib treatment.