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Familial Gastrointestinal Stromal Tumor Syndrome: Phenotypic and Molecular Features in a Kindred

From the Dana-Farber Cancer Institute; Brigham and Women's Hospital; Beth Israel Deaconess Medical Center, Boston, MA; Oregon Health Sciences University Cancer Institute & Portland VA Medical Center, Portland, OR; and Stanford University Medical Center, Stanford, CA

Address reprint requests to Frederick P. Li, MD, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115; e-mail: fli{at}partners.org

PURPOSE: Members of a family with hereditary gastrointestinal stromal tumors (GISTs) and a germline KIT oncogene mutation were evaluated for other potential syndrome manifestations. A tumor from the proband was analyzed to compare features with sporadic GISTs.

PATIENTS AND METHODS: Members of a kindred in which six relatives in four consecutive generations comprised an autosomal dominant pattern of documented GISTs and cutaneous lesions underwent physical examination, imaging studies, and germline KIT analysis. A recurrent GIST from the proband was studied using microarray, karyotypic, immunohistochemical, and immunoblotting techniques.

RESULTS: In addition to evidence of multiple GISTs, lentigines, malignant melanoma, and an angioleiomyoma were identified in relatives. A previously reported gain-of-function missense mutation in KIT exon 11 (T C) that results in a V559A substitution within the juxtamembrane domain was identified in three family members. The proband's recurrent gastric GIST had a 44,XY–14,–22 karyotype and immunohistochemical evidence of strong diffuse cytoplasmic KIT expression without expression of actin, desmin, or S-100. Immunoblotting showed strong expression of phosphorylated KIT and downstream signaling intermediates (AKT and MAPK) at levels comparable with those reported in sporadic GISTs. cDNA array profiling demonstrated clustering with sporadic GISTs, and expression of GIST markers comparable to sporadic GISTs.

CONCLUSION: These studies provide the first evidence that gene expression and mechanisms of cytogenetic progression and cell signaling are indistinguishable in familial and sporadic GISTs. Current investigations of molecularly targeted therapies in GIST patients provide opportunities to increase the understanding of features of the hereditary syndrome, and risk factors and molecular pathways of the neoplastic phenotypes.

Supported in part by a Harry and Elsa Jiler American Cancer Society Clinical Research Professorship, a Merit Review Grant from the Veterans Affairs Administration, the Rubinstein Fund, Leslie's Links Foundation, the Quick Family Sarcoma Research Fund, and the Katz Foundation.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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