SDHB-deficient GISTs and GISTS associated with Carney Triad reveal abnormal mitochondrial ultrastructure: a comparative study including observations in heterozygous Sdhb-deficient mice

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SUN 303-321-Cancer in Endocrine Tissues
Bench to Bedside
Sunday, June 16, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SUN-310
Eva Szarek*1, Maria Tsokos2, Alessio Giubellino1, Mones Abu-Asab3, Evan Ball4, Louis Dye1, Paraskevi Xekouki1, Fabio Rueda Faucz1, Karel Pacak4, J Aidan Carney5 and Constantine A Stratakis1
1National Institutes of Health (NIH), Bethesda, MD, 2NIH, Bethesda, MD, 3NIE/NIH, Bethesda, MD, 4NICHD/NIH, Bethesda, MD, 5Mayo Clinic, Rochester, MN
Carney Triad (CTr), a rare genetic syndrome occurring mainly in young females, describes the association of paragangliomas (PGL) and gastrointestinal stromal tumors (GISTs) with a variety of other lesions including pheochromocytomas and adrenocortical tumors. The gene(s) causing CTr remain(s) unknown. In a separate condition, patients with the dyad of PGL and GISTs (Carney-Stratakis syndrome or CSS) without other tumors contain loss-of-function mutations in succinate dehydrogenase (SDH) subunit genes, most commonly subunit B (the SDHB gene). SDHB, a mitochondrial protein, is one of the proteins functioning at the interface of the tricarboxylic acid cycle and electron transport chain. Mitochondria play significant roles in cellular energy metabolism and free radical generation, thus mitochondrial dysfunction can be correlated with the activity and progression of tumors. SDHB loss-of-function affecting mitochondrial function may lead to tumorigenesis mechanism, potentially upregulating genes that promote adaptation of cells in low-oxygen environments by inducing angiogenesis and glycolysis. We recently identified aberrant mitochondrial morphology in PGLs with SDHx mutations, thereby providing the impetus for our current investigation. We asked whether mitochondrial morphology was comparable in patients with GISTs harboring SDHx mutations, and those without, mainly in CTr patients. 12 patients with CTr-associated GISTs, 2 patients with SDHx mutations (SDHB, SDHC) and 2 patients with PGL (dyad) were included. We also examined the mitochondria in the small intestine of mice with a heterozygous deletion in Sdhb (Sdhb+/-; n=4) by electron microscopy (EM) and classic histochemistry. In patients, epithelioid GISTs were characterized by plump cells containing a centrally located round nucleus and prominent nucleoli. Cytoplasm contained increased mitochondria numbers with highly abnormal structure; mitochondria were devoid of cristae, exhibited structural abnormalities and variable size-some were small and round, others thin and elongated with tubular cristae. Many mitochondria exhibited amorphous fluffy material with membranous whorls or cystic structures. Similar mitochondrial ultrastructure was identified in mice. These data indicate that SDHB-deficient GISTs, and those associated with CTr contain abnormal mitochondrial ultrastucture, thereby contributing to tumor-associated damage.

Nothing to Disclose: ES, MT, AG, MA, EB, LD, PX, FRF, KP, JAC, CAS

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