Li FP et al. (2005) Familial gastrointestinal stromal tumor syndrome: phenotypic and molecular features in a kindred. J Clin Oncol 23: 2735–2743

Recently there has been considerable interest in molecular-targeted therapies for gastrointestinal stromal tumors (GISTs). To understand more about this hereditary syndrome, Li et al. evaluated GISTs with a germline KIT oncogene mutation in a kindred of six family members over four consecutive generations. Members of the kindred underwent physical examination, imaging studies and germline KIT analysis.

Multiple GISTs, lentigines, malignant melanoma and angioleiomyoma were identified from members of the kindred. Molecular studies showed a germline KIT exon 11 (T→C) mutation resulting in a V559A substitution within the juxtamembrane domain in three family members. A recurrent gastric GIST was excised from the proband and studied using microarray, karyotypic, immunohistochemical and immunoblotting techniques. A heterozygous V559A mutation was found to be present. Fifteen metaphase cells were also analyzed from the proband's GIST and all were found to have a similar cytogenetic profile to those found in sporadic GISTs. Immunoblotting demonstrated a profile of phosphorylated protein kinase B (AKT) and mitogen-activated protein kinase (MAPK), but not signal transducer and activator of transcription 5B (STAT5), which is phosphorylated after KIT activation. This finding is also comparable with sporadic GISTs.

The authors conclude that this investigation provides the first evidence that the genetic mechanisms are similar in sporadic and familial GISTs. Further studies are needed to learn more about the epidemiology and environmental risk factors leading to the development of these tumors.