Mutations in exon 11 of c-kit occur preferentially in malignant versus benign gastrointestinal stromal tumors and do not occur in leiomyomas or leiomyosarcomas

Gastrointestinal stromal tumors (GISTs) comprise the largest subset of mese nchymal tumors of the gastrointestinal tract. These neoplasms differ histol ogically and immunohistochemically from typical leiomyomas and leiomyosarco mas. Most GISTs express CDS4 and CD117 (c-kit protein) but not desmin. Rece ntly, gain-of-function mutations of c-kit proto-oncogene have been shown in five solitary GISTs and in tumors and leukocytes from a family with multip le GISTs. An in-frame deletion or a point mutation in elion 11 of c-kit was detected in these cases. Stable transfection of the mutant c-kit complemen tary DNA was also shown to induce malignant transformation of murine lympho id cells, suggesting that the c-kit mutations contribute to tumor developme nt. In this study, we evaluated 43 GISTs and 14 smooth muscle tumors for mu tations in the exon 11 of c-kit by a PCR-assay. Half of the malignant GISTs (12/24) and only one benign GIST (1/19) revealed mutant bands. No mutant b ands were found in 3 leiomyomas and 11 leiomyosarcomas. Sequence analysis c onfirmed the presence of an in-frame deletion of 3-21 bp in all 13 GISTs wi th mutant bands. Wild-type bands from 8 malignant and 11 benign GISTs and 7 smooth muscle tumors without mutant bands were cloned and sequenced. Addit ional mutations were found in 3 malignant and 2 benign GISTs, There mere no mutations in 3 leiomyomas and 4 leiomyosarcomas. The mutation status of ex on 11 did not correlate with immunohistochemically detectable expression of the CD117, as virtually all GISTs with or without such mutations showed CD 117 immunoreactivity. The c-kit mutations occur preferentially in malignant GISTs and might be a clinically useful adjunct marker in the evaluation of GISTs. The conservation of the c-kit mutation pattern, observed in consecu tive lesions from the same patients, suggests that these mutations might be useful tumor markers in monitoring recurrence or minimal residual disease.