Pituitary adenomas constitute about 15% of intracranial tumors, and about one-third of secretory pituitary adenomas produce ACTH. Corticotroph adenomas, a subset of pituitary adenomas staining positive for ACTH, are further categorized into functional (FCA) and silent (SCA) adenomas. FCAs result in central Cushing’s disease (CD) due to the resulting excess of cortisol secretion stimulated by ACTH secretion through hormone disruption while SCAs exhibit mass effects and show increased aggression as compared to its functional counterpart. Obesity and cardiovascular disease, resulting from hypercortisolism in functional adenomas, increase patient morbidity while the invasive nature of silent adenomas increases mortality. Trans sphenoidal surgery (TSS) is the best available treatment option for cotricotroph adenomas, but tumor recurrence is common. We sought to identify differential genetic drivers of sporadic FCAs and SCAs in order to better characterize these tumors and develop novel treatment options. We examined 17 adenomas including 12 FCA and 5 SCA as well as 2 corticotroph hyperplasia (CH) tissue samples. We performed next generation sequencing using OncoPanel versions 2 and 3 on patients operated on at Brigham and Woman’s Hospital between 2008 and 2018 and determined to have a corticotroph adenoma. 3 of 4 FCA patients screened for USP8 mutations contained variants previously described in CD including USP8S718P and USP8S719del. 3 of the 12 FCA patients screened for mutations in ARID1B contained novel variants and 1 patient contained a variant previously described in large intestine adenocarcinomas. Additionally, SNPs were commonly identified in genes responsible for epigenetic regulation implicating histone modification as a therapeutic target. We identified recurrent copy number variants (CNV) in both FCAs and SCAs. Gains of 6p, 20q and 21q were frequently observed in FCAs alongside less common losses in 11p and 19q. Significant amplifications of chromosome 12 were detected in SCAs with single nucleotide deletions in chromosome 10. Furthermore, we report diverging genomic disruption between subtypes associated with functional hormone status. Our data identifies novel genetic drivers in subclasses of corticotroph adenomas and indicate distinct genomic profiles associated with hormone secretion and clinical presentation. Further research is required to better elucidate the role of these genetic variants and how they influence tumorigenesis and hormone production.
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/36530 |
| Date | 12 June 2019 |
| Creators | Johnson, Lauren |
| Contributors | Abreu, Ana, Levy, Simon |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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