Candidate Gene Analysis Of Gastrointestinal Stromal Tumors And Paragangliomas In Patients With Carneys Triad

e12018 Background: Carneys triad (CT) describes the association of paragangliomas (PGLs) with gastrointestinal stromal tumors (GISTs) and pulmonary chondromas (PCH). CT is unique compared to other multiple neoplasia syndromes in that it is an apparently sporadic condition affecting mainly young females. CT is not always complete, with approximately ¼ of patients having all three components, and ½ having only 2 of the three (PCH and GIST). A similar syndrome (the Carney-Stratakis syndrome) is characterized by the familial association of GIST and PGL and can be inherited as an autosomal-dominant disorder due to mutations in SDHB,-C, and –D. The association of three rare tumors is strongly suggestive of a genetic disorder, yet no gene has been linked to CT. Using a novel CGH method, SOMATICS, chromosome 1p losses were determined to be frequent in both PGLs and GISTs from CT patients. Recent data implicate ARID1A as a tumor-suppressor gene frequently disrupted in ovarian clear-cell and endometrioid carcinomas. Using a candidate gene-based approach, we sequenced tumor suppressor genes in GISTs and PGLs from patients with CT. Methods: Gene candidacy was determined either by genome location (ARID1A 1p35.3), or potentially oncogenic pathway-defects in mitochondrial complex II activity (SDHAF1). Coding regions and exon-intron boundaries for ARID1A and SDHAF1 were PCR-amplified and sequenced using the Sanger method on tumor DNA from 13 patients with CT (7 paragangliomas and 11 GISTs). Results: All DNA specimens were confirmed to be negative for mutations in SDHA, SDHB, SDHC, SDHD, KIT and PDGFRA. Sequencing analysis revealed only polymorphisms, but no somatic mutations in both ARID1A and SDHAF1. Conclusions: Although the loss of chromosome 1p is a frequent feature, the ARID1A tumor suppressor gene that is located in this region, does not seem to harbor sequence alterations. These data indicate that another gene (or genes) is probably responsible for the tumor genesis in patients with CT. Further research using next generation sequencing is ongoing in our institution.