Endocrine Abstracts (2010) 22 S8.2

New multiple endocrine neoplasias: endocrine tumors associated with gastrointestinal stromal tumors (GISTs)

Constantine Stratakis

NIH, Bethesda, Maryland, USA.

Carney triad (CT) describes the association of paragangliomas (PGLs) with gastrointestinal stromal tumors (GISTs) and pulmonary chondromas (PCH). In addition to pheochromocytomas, a number of other lesions have been described in the condition including pheochromocytomas, esophageal leiomyomas, and adrenocortical adenomas; CT, therefore, is a novel form of multiple endocrine neoplasia (MEN). CT appears to be a genetic condition with a female predilection. Inactivating mutations of the mitochondrial complex II succinate dehydrogenase (SDH) enzyme subunits SDHB, SDHC and SDHD have been found in familial and sporadic PGLs, and gain-of-function mutations of the oncogenes c-kit (KIT) and platelet-derived growth factor receptor A (PDGFRA) cause sporadic and familial GISTs. Comparative genomic hybridization (CGH) revealed a number of DNA copy number changes. The most frequent and greatest contiguous change was a deletion within the 1pcen13-q21 region, which harbors the SDHC gene. Another frequent change was loss of 1p. Although GISTs showed more frequent losses of 1p than PGLs, the pattern of chromosomal changes was similar in the two tumors despite their different tissue origin and histology; the findings were consistent with a common genetic etiology of these two tumors in CT. In a separate condition, in which the association (or dyad) of GISTs with PGLs is inherited in an autosomal dominant manner (Carney-Stratakis syndrome, CSS), germline mutations of the SDHB, SDHC and SDHD genes (but not KIT or PDFGRA) were found; GISTs in this condition were caused by SDH deficiency. In conclusion, CT is a novel MEN syndrome whose genetic defect remains elusive. CSS is caused by SDH defects, suggesting that sarcomas (GISTs) can be caused by defective mitochondrial oxidation, consistent with recent data implicating this enzyme in a variety of endocrine and other tumors. The above have clinical implications i) for patients with GISTs that are cKIT- and PDGFRA-mutation negative: these tumors are usually resistant to treatment with currently available tyrosine kinase inhibitor and may be part of a syndrome such as CT or CSS; and ii) for patients with an inherited PGL syndrome: family history should be explored to identify any other tumors in the family, and in particular other endocrine lesions and GISTs.

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