A familial germline mutation in KIT associated with achalasia, mastocytosis and gastrointestinal stromal tumors shows response to kinase inhibitors

Abstract Background Activating mutations of the tyrosine kinase receptor KIT have been described in both mastocytosis and gastrointestinal stromal tumors (GIST), but are usually found in separate domains and often respond differently to signal transduction inhibitors. We describe here a large family with both GIST, mastocytosis, and achalasia. Affected family members have a unique activating mutation in exon 9 of KIT which show promise to a novel signal transduction inhibitor. Methods Clinical data was collected from 15 family members, 7 of whom were variably affected with GIST, achalasia and mastocytosis. DNA was prepared from WBC of 12 subjects (6 affected and 6 unaffected) and exons 9, 11, 13 and 17 of KIT were amplified by PCR and directly sequenced. Results A unique activating single base pair mutation in the extracellular domain of KIT was found in all 6 affected subjects resulting in a K>I amino acid change at codon 509. Conclusions In the family reported here, a unique mutation in the extracellular domain leads to receptor activation resulting in GIST and mastocytosis as well as achalasia. Initial data suggests that this activation can be suppressed by signal transduction inhibitors and these patients may benefit from such therapy.