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• W176477424 abstract "In order to determine whether succinate dehydrogenase (SDH) deficiency plays a role in sporadic, non-familial pituitary adenomas, we analyzed 80 pituitary adenomas for SDH deficiency from patients without familial tumor syndromes or without known SDH deficiency-associated neoplasms. SDH deficiency was determined by immunohistochemical (IHC) stains for SDHB since the loss of any of the four SDH subunits results in the loss of SDHB expression. Three pituitary adenomas showed complete loss of SDHB staining, and of these two also showed loss of SDHA staining. We further characterized these adenomas by looking at Ki67, IGF1R, and 5hmC levels via IHC. SDHx-deficient (non-SDHA deficient) tumors had a Ki67 proliferation index higher than non-SDH deficient pituitary tumors while SDHA-deficient tumors had Ki67 indices similar to non-SDH deficient tumors. IGF1R IHC staining was similar across all subsets. All SDH-deficient subtypes showed a loss of 5-hydroxymethylcytosine nuclear IHC staining. These findings suggest that SDH deficiency promotes tumorigenesis of pituitary adenomas through accumulation of succinate resulting in changes in the epigenome, specifically resulting in a hypermethylated state. INTRODUCTION Pituitary adenomas are relatively common neoplasms of the central nervous system found in approximately 16% of the population. Among all intracranial neoplasms, pituitary adenomas account for 10% of pathological new growths and are the most common neoplasms within the sella. These tumors are categorized based on size, invasiveness, secretory capacity and specificity, and are almost invariably derived from the adenohypophysis. Treatment is primarily surgical. The genesis of pituitary adenomas is still largely unresolved despite the association of these tumors with syndromes that have known progenitor mutations. Several families with germline mutations in the genes encoding SDH subunits have been associated with pituitary adenomas and SDH deficiency is pro-oncogenic in a variety of other tumors, including extra-adrenal paragangliomas, a subset of gastrointestinal stromal tumors, pheochromocytomas, and renal cancers. Familial and genetic pituitary adenomas, however, account for only a small percentage of all pituitary adenomas (~5%). While SDH-deficient tumors typically occur in the setting of germline mutations, SDH-deficient tumors can occur sporadically. The proposed mechanisms for tumorigenesis in SDH deficiency are loss-of-function mutations in or epigenetic silencing of SDH subunit genes that then cause the intermediate metabolite succinate to accumulate. Succinate build-up can result in a pseudohypoxic state within the cell which, through HIFα, upregulates expression of angiogenic factors and enzymes that aid in cell survival. Another possible mechanism of tumorigenesis related to succinate accumulation is inhibition of α-ketoglutarate-dependent dioxygenases, particularly the ten eleven translocaton (TET) family of 5-methylcytosine (5mC) hydroxylases, which produces epigenetic alterations. In particular, SDH-deficient tumors have elevated hypermethylation compared to non-SDH deficient counterparts, suggested by the lower levels of 5hydroxymethylcytosine (5-hmC). METHODS All SDH-deficient pituitary adenomas were described clinically as large. The two SDHA deficient adenomas were also invasive, with one growing into the nasal sinuses and the other extending into the cavernous sinus. Tissue was fixed in formalin and embedded in paraffin blocks. 5 micron-thick sections of representative pituitary adenomas were punched out of these blocks and assembled into tissue arrays with 40-45 samples per slide (Figure 2). Arrays were analyzed by IHC for expression of SDHA, SDHB, Ki67, IGF1R, and 5-hmC by standard methods (Figure 3). RESULTS" @default.
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• W176477424 date "2014-01-01" @default.
• W176477424 modified "2023-09-27" @default.
• W176477424 title "Succinate Dehydrogenase Deficiency in Sporadic Pituitary Adenomas: A Potential Mechanism for Tumorigenesis" @default.
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