Familial Gastrointestinal Stromal Tumors and Germ-Line Mutations

Abstract

Familial Gastrointestinal Stromal Tumors and Germ-Line MutationsTo the Editor: Gastrointestinal stromal tumors may be sporadic or inherited in an autosomal dominant manner, alone or as a component of a syndrome associated with other tumors, such as in the context of neurofibromatosis type 1. 1 We have described seven male and five female patients (median age, 23 years) from five unrelated families who had both gastrointestinal stromal tumors and paragangliomas.Susceptibility to the tumors was inherited in an apparently autosomal dominant manner, with incomplete penetrance. 2 This condition has been referred to as "the dyad of paraganglioma and gastrointestinal stromal tumors" or the "Carney-Stratakis syndrome" (or "Carney-Stratakis dyad"). 3Germ-line mutations of the genes encoding succinate dehydrogenase subunits B, C, and D (SDHB, SDHC, and SDHD) have been described in inherited paraganglioma and pheochromocytoma 4 but not in familial gastrointestinal tumors.The family history of a kindred with multiple paragangliomas and a germ-line SDHB mutation included a person with a gastrointestinal stromal tumor, 5 but neither blood nor tissue specimens from this patient were studied for SDHB abnormalities.We identified six germ-line SDHB, SDHC, and SDHD mutations in patients with the dyad (Fig. 1).Gastrointestinal stromal tumors from the patients showed allelic losses around the chromosomal loci of the succinate dehydrogenase subunit.The patients did not have mutations of KIT or the gene for platelet-derived growth factor receptor alpha (PDGFRA), which have been associated with gastrointestinal tumors. 1 We conclude that familial gastrointestinal stromal tumors may be caused by mutations of the succinate dehydrogenase subunit genes SDHB, SDHC, and SDHD, and abdominal paragangliomas associated with gastrointestinal tumors may be caused uniquely by SDHC mutations.